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Xu JX, Su YX, Chen YY, Huang YY, Chen ZS, Peng YC, Qi LN. Immune infiltration landscape and potential drug-targeted implications for hepatocellular carcinoma with 'progression/hyper-progression' recurrence. Ann Med 2025; 57:2456113. [PMID: 39865865 PMCID: PMC11774162 DOI: 10.1080/07853890.2025.2456113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 12/20/2024] [Accepted: 01/08/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) recurrence was previously characterized into four types, and patients with progression/hyper-progression recurrence (type III-IV) have an extremely poor prognosis. However, the immune background of resectable HCC, particularly in patients who experience recurrence, remains underexplored. Therefore, this study aimed to describe the immune landscape of resectable HCC, especially postoperative type III-IV recurrent HCC, and explore potential immune-targeted anti-relapse strategies for treated populations. METHODS The differences in gene expression in patients with recurrent HCC (type I-II (solitary or multi-intrahepatic oligo recurrence) vs. type III-IV) were investigated using bulk sequencing. Multiple immune infiltration methods (single-sample gene set enrichment analysis (GSEA), Microenvironment Cell Populations-counter and ESTIMATE) were used, and patients were divided into four groups to identify four distinct immune subtypes: immune-enrichment/matrix-poor (IE1), immune-enrichment/matrix-rich (IE2), immune intermediate/matrix-rich (ITM) and immune desert/matrix-poor (ID). Co-expression and protein interaction analyses were used to identify characteristic genes in ITM closely associated with type III-IV recurrence, which was matched with drug targets for Huaier granules (HG) and lenvatinib. Virtual docking was used to identify potential therapeutic targets, and the results were verified using single-nuclei RNA sequencing and histological analysis. RESULTS ITM was closely related to type III-IV recurrence and exhibited immunotherapy potential. The potential efficacy of inhibiting CCNA2, VEGFA, CXCL8, PLK2, TIMP1, ITGB2, ALDOA, ANXA5 and CSK in ITM reversal was determined. Molecular docking demonstrated that the proteins of these genes could bind to HG or lenvatinib. The immunohistochemical findings demonstrated differential VEGFA (p < .01) and PLK2 (p < .001) expression in ITM type and ID in type III-IV recurrent HCC. CONCLUSIONS Three primary immunotypes of resectable HCC (IE2, ITM and ID) were identified, and HG and lenvatinib could potentially overcome immune checkpoint blockade (ICB) resistance in ITM patients with HCC, particularly those classified as type III-IV.
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Affiliation(s)
- Jing-Xuan Xu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Yue-Xiang Su
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Yuan-Yuan Chen
- Department of Ultrasound, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yi-Yue Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
| | - Zu-Shun Chen
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yu-Chong Peng
- Department of General Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Lu-Nan Qi
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumour, Ministry of Education, Nanning, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Nanning, China
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2
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Yao J, Ning B, Ding J. The gut microbiota: an emerging modulator of drug resistance in hepatocellular carcinoma. Gut Microbes 2025; 17:2473504. [PMID: 40042184 PMCID: PMC11901387 DOI: 10.1080/19490976.2025.2473504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 11/08/2024] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
Liver cancer is usually diagnosed at an advanced stage and is the third most common cause of cancer-related death worldwide. In addition to the lack of effective treatment options, resistance to therapeutic drugs is a major clinical challenge. The gut microbiota has recently been recognized as one of the key factors regulating host health. The microbiota and its metabolites can directly or indirectly regulate gene expression in the liver, leading to gut-liver axis dysregulation, which is closely related to liver cancer occurrence and the treatment response. Gut microbiota disturbance may participate in tumor progression and drug resistance through metabolite production, gene transfer, immune regulation, and other mechanisms. However, systematic reviews on the role of the gut microbiota in drug resistance in liver cancer are lacking. Herein, we review the relationships between the gut microbiota and the occurrence and drug resistance of hepatocellular carcinoma, summarize the emerging mechanisms underlying gut microbiota-mediated drug resistance, and propose new personalized treatment options to overcome this resistance.
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Affiliation(s)
- Jiali Yao
- Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, China
| | - Beifang Ning
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jin Ding
- Clinical Cancer Institute, Center for Translational Medicine, Naval Medical University, Shanghai, China
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3
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Ma C, Yu X, Zhang X, Su L, Jiang O, Cui R. Combination of radiotherapy and ICIs in advanced hepatocellular carcinoma: A systematic review of current evidence and future prospects (Review). Oncol Lett 2025; 30:342. [PMID: 40438865 PMCID: PMC12117537 DOI: 10.3892/ol.2025.15088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 03/24/2025] [Indexed: 06/01/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health concern because of its rising prevalence and high fatality rates. Conventional treatments for advanced HCC (aHCC) have limited success, emphasizing the need for novel treatment options. Radiotherapy (RT) treatments, such as stereotactic body radiation and proton therapy, improve local tumor management via precision targeting. Moreover, immune checkpoint inhibitors (ICIs) that target the programmed cell death protein 1(PD-1)/PD ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) pathways have promise for systemic antitumor effectiveness. The combination of RT and ICIs takes advantage of their complementary mechanisms: RT kills immunogenic cells and controls the tumor microenvironment to increase antigen presentation, whereas ICIs enhance and maintain antitumor immune responses. This combination enhances tumor regression and immune response in aHCC, improving response rate and progression-free survival with manageable safety. The present review aimed to summarize the rationale for combining RT + ICIs in patients with aHCC and clinical outcomes, as well as ways to enhance this combination technique. The combination of these models is a promising technique for improving outcomes for patients with aHCC and warrants further investigation.
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Affiliation(s)
- Cheng Ma
- Department of Oncology, The First People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China
| | - Xinlin Yu
- Department of Oncology, The Affiliated Hospital of Chengdu University, Chengdu, Sichuan 610000, P.R. China
| | - Xialin Zhang
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Lihong Su
- Department of Oncology, The First People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China
| | - Ou Jiang
- Department of Oncology, The First People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China
| | - Ran Cui
- Department of Oncology, The First People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China
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4
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Xu P, Hong C, Liu L, Xiao L. PD-1/PD-L1 blockade therapy in hepatocellular carcinoma: Current status and potential biomarkers. Biochim Biophys Acta Rev Cancer 2025; 1880:189334. [PMID: 40280499 DOI: 10.1016/j.bbcan.2025.189334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 04/21/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death and the sixth most prevalent cancer worldwide. However, most patients with HCC are at an advanced stage at the time of clinical diagnosis, making surgery impossible. In the past, targeted therapeutic drugs such as sorafenib and lenvatinib were the main treatments. With recent breakthroughs in medicine, immunotherapy, particularly immune checkpoint inhibitors (ICIs), has garnered interest and has been extensively studied for clinical treatment. In addition to single-agent therapies, combination regimens involving ICIs have also been developed. Despite this progress, not all patients with HCC benefit from immunotherapy. Therefore, to improve the treatment response rates, it is crucial to identify patients with HCC who are suitable for immunotherapy. The exploration and validation of markers to predict the outcomes of immunotherapeutic treatments in patients with HCC are of clinical importance. In this article, we provide a comprehensive review of research progress in immunotherapy, particularly ICIs and combination therapies, for HCC. Furthermore, we summarize the clinical indicators and tumor markers discovered in recent years to forecast immunotherapy outcomes in patients with HCC. We also outline predictive markers for the occurrence of immune-related adverse events in patients with HCC receiving immunotherapy and discuss future research directions in the immunotherapeutic treatment landscape.
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Affiliation(s)
- Peishuang Xu
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Chang Hong
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Li Liu
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Lushan Xiao
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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Pettas T, Lachanoudi S, Karageorgos FF, Ziogas IA, Fylaktou A, Papalois V, Katsanos G, Antoniadis N, Tsoulfas G. Immunotherapy and liver transplantation for hepatocellular carcinoma: Current and future challenges. World J Transplant 2025; 15:98509. [DOI: 10.5500/wjt.v15.i2.98509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/03/2024] [Accepted: 11/07/2024] [Indexed: 02/21/2025] Open
Abstract
Despite existing curative options like surgical removal, tissue destruction techniques, and liver transplantation for early-stage hepatocellular carcinoma (HCC), the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies. This review critically assesses the dynamic treatment panorama for HCC, focusing specifically on the burgeoning role of immunotherapy in two key contexts: early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy. It delves into the unique immunobiology of the liver and HCC, highlighting tumor-mediated immune evasion mechanisms. Analyzing the diverse immunotherapeutic approaches including checkpoint inhibitors, cytokine modulators, vaccines, oncolytic viruses, antigen-targeting antibodies, and adoptive cell therapy, this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring. Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC, current research is actively exploring the safety and effectiveness of diverse immunotherapeutic approaches through ongoing clinical trials. The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant, highlighting the need for careful patient selection, meticulous monitoring, and novel strategies to mitigate post-transplant complications. Finally, this review delves into the latest findings from the clinical research landscape and future directions in HCC management, paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.
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Affiliation(s)
- Theodoros Pettas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Sofia Lachanoudi
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Filippos F Karageorgos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Vassilios Papalois
- Department of Transplant Surgery, Imperial College Renal and Transplant Centre, London W12 0HS, United Kingdom
| | - Georgios Katsanos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| | - Nikolaos Antoniadis
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
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Bradbury M, Gabara A, Pond GR, Meyers BM, Kartolo A. Time toxicity of nivolumab in metastatic head and neck squamous cell carcinoma patients: a single-institution experience. Immunotherapy 2025:1-7. [PMID: 40514043 DOI: 10.1080/1750743x.2025.2518913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 06/10/2025] [Indexed: 06/16/2025] Open
Abstract
BACKGROUND Treatment of platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (r/mHNSCC) involves immune-checkpoint inhibitors. Time toxicity (TT) is an emerging metric with implications for patient quality of life and decision-making. We sought to evaluate TT associated with nivolumab in these patients. METHODS This is a retrospective single-institution review of patients with platinum-refractory r/mHNSCC seen at an academic cancer center between 1 January 2018 to 31 December 2022 in Ontario, Canada. Primary outcome is TT, defined as any number of days spent undergoing cancer-related activities. RESULTS Of 56 patients evaluated, median age was 63 years (33-85) and 84% were male. Median overall survival (OS) and grade 3 immune-toxicities were 7.6 months and 6.2%, respectively. Median TT was 24 days (1-109), accounting for 7.6% of OS. TT accounted for 14.9% of OS in poor responders. TT accounted for only 4-6% for patients who survived more than a year. CONCLUSIONS Our study provides an important and underexplored patient-centered metric in TT, especially in the context of incurable HNSCC with abysmal survival outcome. Our findings suggest that TT varies significantly between responders and non-responders. Duration of TT should be discussed with patients in shared decision-making when discussing palliative nivolumab.
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Affiliation(s)
- Michelle Bradbury
- Department of Medicine, Division of Medical Oncology, Juravinski Cancer Centre and McMaster University, Hamilton, ON, Canada
| | - Adam Gabara
- Department of Medicine, Division of Radiation Oncology, Juravinski Cancer Centre and McMaster University, Hamilton, ON, Canada
| | - Gregory R Pond
- Department of Oncology, McMaster University, Hamilton, ON, Canada
- Escarpment Cancer Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada
| | - Brandon M Meyers
- Department of Medicine, Division of Medical Oncology, Juravinski Cancer Centre and McMaster University, Hamilton, ON, Canada
- Escarpment Cancer Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada
| | - Adi Kartolo
- Department of Medicine, Division of Medical Oncology, Juravinski Cancer Centre and McMaster University, Hamilton, ON, Canada
- Escarpment Cancer Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada
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7
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Huang JC, Tong XL, Xiang MSW, Boumelhem BB, Foulis DP, Zhang M, McKenzie CA, McCaughan GW, Reinheckel T, Zhang HE, Gorrell MD. Dipeptidyl peptidase 9 (DPP9) depletion from hepatocytes in experimental primary liver cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167819. [PMID: 40187163 DOI: 10.1016/j.bbadis.2025.167819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 03/13/2025] [Accepted: 03/25/2025] [Indexed: 04/07/2025]
Abstract
Dipeptidyl peptidase 9 (DPP9) is an indispensable intracellular protease. Among its many molecular functions is suppression of the NLRP1 inflammasome. Inhibitors targeting all four proteases of the DPP4 family, including DPP9, can reduce tumour burden, including in mouse liver. To explore hepatocyte DPP9 in experimental hepatocellular carcinoma (HCC), we generated hepatocyte-specific DPP9-KO mice by crossing albumin-Cre mice with DPP9 floxed mice and treated sequentially with diethylnitrosamine, then with thioacetamide combined with an atherogenic high-fat diet until 28 weeks of age. DPP9-KO mice had less body, liver and subcutaneous adipose tissue mass, lower fasting plasma glucose and fewer small macroscopic liver nodules compared to DPP9-WT control mice. However, there were no differences in the total number of macroscopic liver nodules, or of microscopic tumour burden, inflammation, fibrosis or steatosis. Consistent with the known function of DPP9 to suppress NLRP1 activation, activated caspase-1 protein and inflammation markers Nfkbib, Cxcl10 and Ccl5 were elevated in DPP9-KO liver. The tumour suppressor protein p53 was increased and the autophagy proteins beclin1, LC3B and p62 were altered. In conclusion, hepatocyte-specific DPP9 gene deletion in experimental primary liver cancer improved energy metabolism and may reduce liver cancer initiation, via mechanisms that may include increased autophagy and tumour suppression.
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MESH Headings
- Animals
- Hepatocytes/pathology
- Hepatocytes/metabolism
- Hepatocytes/enzymology
- Mice
- Mice, Knockout
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism
- Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/deficiency
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/chemically induced
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Male
- Liver Neoplasms/pathology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Diet, High-Fat/adverse effects
- Mice, Inbred C57BL
- Inflammasomes/metabolism
- Liver/pathology
- Liver/metabolism
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Affiliation(s)
- JiaLi Carrie Huang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Xinlin Linda Tong
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Michelle Sui Wen Xiang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Badwi B Boumelhem
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Diarmid P Foulis
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - MingChang Zhang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Catriona A McKenzie
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Geoffrey W McCaughan
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
| | - Thomas Reinheckel
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), partner site Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Centre for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany
| | - Hui E Zhang
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Mark D Gorrell
- Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
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Scheiner B, Kang B, Balcar L, Radu IP, Reiter FP, Adžić G, Guo J, Gao X, Yuan X, Cheng L, Gorgulho J, Schultheiss M, Peeters F, Hucke F, Ben Khaled N, Piseddu I, Philipp A, Sinner F, D'Alessio A, Pomej K, Saborowski A, Bathon M, Schwacha-Eipper B, Zarka V, Lampichler K, Nishida N, Lee PC, Krall A, Saeed A, Himmelsbach V, Tesini G, Huang YH, Vivaldi C, Masi G, Vogel A, Schulze K, Trauner M, Djanani A, Stauber R, Kudo M, Parikh ND, Dufour JF, Prejac J, Geier A, Bengsch B, von Felden J, Venerito M, Weinmann A, Peck-Radosavljevic M, Finkelmeier F, Dekervel J, Ji F, Wang HW, Rimassa L, Pinato DJ, Bouattour M, Chon HJ, Pinter M. Outcome and management of patients with hepatocellular carcinoma who achieved a complete response to immunotherapy-based systemic therapy. Hepatology 2025; 81:1714-1727. [PMID: 39643944 DOI: 10.1097/hep.0000000000001163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 09/12/2024] [Indexed: 12/09/2024]
Abstract
BACKGROUND AND AIMS The outcome of patients with HCC who achieved complete response (CR) to immune-checkpoint inhibitor (ICI)-based systemic therapies is unclear. APPROACH AND RESULTS Retrospective study of patients with HCC who had CR according to modified Response Evaluation Criteria in Solid Tumors (CR-mRECIST) to ICI-based systemic therapies from 28 centers in Asia, Europe, and the United States. Of 3933 patients with HCC treated with ICI-based noncurative systemic therapies, 174 (4.4%) achieved CR-mRECIST, and 97 (2.5%) had CR according to RECISTv1.1 (CR-RECISTv1.1) as well. The mean age of the total cohort (male, 85%; Barcelona-Clinic Liver Cancer-C, 70%) was 65.9±9.8 years. The majority (83%) received ICI-based combination therapies. Median follow-up was 32.2 (95% CI: 29.9-34.4) months. One- and 3-year overall survival rates were 98% and 86%. One- and 3-year recurrence-free survival rates were excellent in patients with CR-mRECIST-only and CR-RECISTv1.1 (78% and 55%; 70% and 42%). Among patients who discontinued ICIs for reasons other than recurrence, those who received immunotherapy for ≥6 months after the first mRECIST CR had a longer recurrence-free survival than those who discontinued immunotherapy earlier ( p =0.008). Of 9 patients who underwent curative surgical conversion therapy, 8 (89%) had pathological CR (CR-RECISTv1.1, n= 2/2; CR-mRECIST-only, n= 6/7). CONCLUSIONS Overall survival and recurrence-free survival of patients with CR-mRECIST-only and CR-RECISTv1.1 were excellent, and 6 of 7 patients with CR-mRECIST-only who underwent surgical conversion therapy had pathological CR. Despite potential limitations, these findings support the use of mRECIST in the context of immunotherapy for clinical decision-making. When considering ICI discontinuation, treatment for at least 6 months beyond CR seems advisable.
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Affiliation(s)
- Bernhard Scheiner
- Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Beodeul Kang
- Department of Internal Medicine, Division of Medical Oncology, CHA Bundang Medical Centre, CHA University, Seongnam, Republic of Korea
| | - Lorenz Balcar
- Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Iuliana-Pompilia Radu
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Florian P Reiter
- Department of Medicine II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany
| | - Gordan Adžić
- Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Jiang Guo
- Department of Oncology Interventional Radiology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xu Gao
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiao Yuan
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Long Cheng
- Department of Oncology Interventional Radiology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Joao Gorgulho
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany
| | - Michael Schultheiss
- Department of Medicine II, Medical Center-University of Freiburg, Germany, Faculty of Medicine, University of Freiburg, Germany
| | - Frederik Peeters
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Herestraat, Leuven, Belgium
| | - Florian Hucke
- Internal Medicine and Gastroenterology (IMuG), including Centralized Emergency Service (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Ignazio Piseddu
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Alexander Philipp
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Friedrich Sinner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von Guericke University Hospital, Magdeburg, Germany
| | - Antonio D'Alessio
- Department of Surgery and Cancer, Division of Cancer, Imperial College London, London, United Kingdom
- Department of Translational Medicine, Division of Oncology, University of Piemonte Orientale, Novara, Italy
| | - Katharina Pomej
- Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Anna Saborowski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Melanie Bathon
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Birgit Schwacha-Eipper
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Valentina Zarka
- Department of Medicine II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany
| | - Katharina Lampichler
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Pei-Chang Lee
- Department of Medicine, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Anja Krall
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh (UPMC), Pittsburgh, Pennsylvania, USA
| | - Vera Himmelsbach
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Giulia Tesini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Yi-Hsiang Huang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan
- Healthcare and Services Center, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Caterina Vivaldi
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Gianluca Masi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Arndt Vogel
- Division of Gastroenterology and Hepatology, Toronto General Hospital, Toronto, Canada
- Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada
- Hannover Medical School, Hannover, Germany
| | - Kornelius Schulze
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Michael Trauner
- Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Angela Djanani
- Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Rudolf Stauber
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Juraj Prejac
- Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia
- University of Zagreb, School of Dental Medicine, Zagreb, Croatia
| | - Andreas Geier
- Department of Medicine II, Division of Hepatology, University Hospital Würzburg, Würzburg, Germany
| | - Bertram Bengsch
- Department of Medicine II, Medical Center-University of Freiburg, Germany, Faculty of Medicine, University of Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Johann von Felden
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marino Venerito
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von Guericke University Hospital, Magdeburg, Germany
| | - Arndt Weinmann
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Markus Peck-Radosavljevic
- Internal Medicine and Gastroenterology (IMuG), including Centralized Emergency Service (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Fabian Finkelmeier
- Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Jeroen Dekervel
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Herestraat, Leuven, Belgium
| | - Fanpu Ji
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China
| | - Hung-Wei Wang
- Department of Internal Medicine, Center for Digestive Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - David J Pinato
- Department of Surgery and Cancer, Division of Cancer, Imperial College London, London, United Kingdom
- Department of Translational Medicine, Division of Oncology, University of Piemonte Orientale, Novara, Italy
| | - Mohamed Bouattour
- Liver Cancer and Innovative Therapy, AP-HP, Hôpital Beaujon, Clichy, France
| | - Hong Jae Chon
- Department of Internal Medicine, Division of Medical Oncology, CHA Bundang Medical Centre, CHA University, Seongnam, Republic of Korea
| | - Matthias Pinter
- Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Department of Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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Zhang D, Zhu Y, Shen Z, Ma S, Liu S, Lu Z. Immunosenescence and immunotherapy in elderly patients with hepatocellular carcinoma. Semin Cancer Biol 2025; 111:60-75. [PMID: 40020977 DOI: 10.1016/j.semcancer.2025.02.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 02/11/2025] [Accepted: 02/17/2025] [Indexed: 03/03/2025]
Abstract
Liver cancer, more specifically hepatocellular carcinoma (HCC), is a global health issue and one of the dominant causes of cancer death around the world. In the past few decades, remarkable advances have been achieved in the systemic therapy of HCC. Immune checkpoint inhibitors (ICIs) have become a therapy mainstay for advanced HCC and have shown promise in the neoadjuvant therapy before resection. Despite these significant advancements, the compositions and functions of the immune system occur various alterations with age, called "immunosenescence", which may affect the antitumor effects and safety of ICIs, thus raising concerns that immunosenescence may impair elderly patients' response to ICIs. Therefore, it is important to learn more about the immunosenescence characteristics of elderly patients. However, the real-world elderly HCC patients may be not accurately represented by the elderly patients included in the clinical trials, affecting the generalizability of the efficacy and safety profiles from the clinical trials to the real-world elderly patients. This review summarizes the characteristics of immunosenescence and its influence on HCC progression and immunotherapy efficacy as well as provides the latest progress in ICIs available for HCC and discusses their treatment efficacy and safety on elderly patients. In the future, more studies are needed to clarify the mechanisms of immunosenescence in HCC, and to find sensitive screening tools or biomarkers to identify the patients who may benefit from ICIs.
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Affiliation(s)
- Dengyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Yan Zhu
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zhengchao Shen
- Department of General Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241001, China
| | - Shuoshuo Ma
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Sihua Liu
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China
| | - Zheng Lu
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China.
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10
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Tang M, Liu T, Zhang Y, Ding J. Efficacy and safety of pembrolizumab in the treatment of advanced hepatocellular carcinoma: a systematic review and meta-analysis. Eur J Clin Pharmacol 2025; 81:815-830. [PMID: 40172662 DOI: 10.1007/s00228-025-03829-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 03/21/2025] [Indexed: 04/04/2025]
Abstract
BACKGROUND The efficacy and safety of pembrolizumab in treating advanced hepatocellular carcinoma (HCC) are inconsistent across studies. This study sheds light on the efficacy and safety of pembrolizumab in advanced HCC patients. METHODS Several databases were comprehensively searched up to January 13, 2025, to identify studies assessing pembrolizumab for advanced HCC. Outcome indicators included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), rash, adverse events (AEs), and severe adverse events (SAEs). Pooled effects were estimated through hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs). R 4.4.1. was employed for statistical analyses. RESULTS Twenty-two studies involving 2964 patients were encompassed. Meta-analysis indicated that pembrolizumab demonstrated an ORR of 28% in single-arm analyses. Pembrolizumab significantly improved ORR in comparison to placebo (OR = 2.57, 95% CI: 1.32-5.03) but showed no significant advantage over nivolumab. Pembrolizumab markedly enhanced PFS (HR = 0.76, 95% CI: 0.69-0.85) and OS (HR = 0.78, 95% CI: 0.70-0.88) compared to placebo, but no significant differences were observed when compared to nivolumab. Pembrolizumab significantly raised the risk of rash in comparison to placebo (OR = 2.27, 95% CI: 1.55-3.31) but showed no significant difference versus nivolumab. The pembrolizumab group showed a higher incidence of AEs (OR = 1.94, 95% CI: 1.42-2.64) and SAEs (OR = 2.10, 95% CI: 1.04-4.25) than the placebo group, with no significant difference between pembrolizumab and nivolumab. CONCLUSIONS This study proves that pembrolizumab may have promising therapeutic effects in patients with advanced HCC, although no clear advantage over nivolumab was observed. The occurrence of AEs warrants attention in clinical practice.
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MESH Headings
- Humans
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Liver Neoplasms/drug therapy
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/therapeutic use
- Treatment Outcome
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Affiliation(s)
- Mingyang Tang
- Health Science Center, Hubei Minzu University, Enshi Hubei, 445000, China
| | - Tao Liu
- Hepatobiliary Pancreatic Spleen Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 158 Wuyang Avenue, Wuyangba Street, Enshi Hubei, Hubei Province, 445000, China
| | - Yukun Zhang
- Abdominal Oncology Department, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Hubei, 445000, China
| | - Jun Ding
- Hepatobiliary Pancreatic Spleen Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 158 Wuyang Avenue, Wuyangba Street, Enshi Hubei, Hubei Province, 445000, China.
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11
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Cabibbo G, Rimassa L, Lamarca A, Masi G, Daniele B, Pinato DJ, Casadei-Gardini A. The present and the future of immunotherapy in hepatocellular carcinoma and biliary tract cancers. Cancer Treat Rev 2025; 137:102955. [PMID: 40373702 DOI: 10.1016/j.ctrv.2025.102955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2025] [Accepted: 05/06/2025] [Indexed: 05/17/2025]
Abstract
Hepatobiliary malignancies encompass a spectrum of invasive carcinomas arising in the liver [hepatocellular carcinoma (HCC), bile ducts [intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (EHC)] and the gallbladder. These malignancies represent a growing global health burden, with rising incidence and mortality rates and their overall prognosis remains poor because many patients present with advanced unresectable disease at diagnosis. In recent years, significant advancements in understanding HCC immunogenicity have reshaped the therapeutic scenario of advanced HCC with the immunotherapy revolutionizing the current HCC treatment landscape and patients' prognosis. Moreover, the addition of immunotherapy to chemotherapy has recently established a new standard of care first-line treatment for patients with biliary tract cancers (BTCs) who had historically few therapeutic options. Currently, immunotherapy and immune checkpoint inhibitor (ICI)-based regimens stand as a valuable and practice-changing options in both HCC and BTC management. The mounting recent evidence supporting immunotherapy's survival benefit demands clinicians to stay updated with a rapidly evolving treatment landscape as well as gain knowledge about patient selection, response rate compared with other systemic treatments and immune-mediated adverse events (imAEs) management. A panel of international Experts, comprising hepatologists and oncologists, gathered to explore the challenges in effectively integrating immunotherapy in routine clinical practice. The aim of this review is to present the Experts' insights to inform treatment choice in HCC and BTC with a special emphasis on the role of currently available ICI-based therapies in shifting treatment paradigms and potentially reversing the natural course of these two deadly malignancies.
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Affiliation(s)
- Giuseppe Cabibbo
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties PROMISE, University of Palermo, Piazza delle Cliniche n 2, 90127 Palermo, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy; Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via A. Manzoni 56, 20089 Rozzano, Milan, Italy.
| | - Angela Lamarca
- Department of Oncology - OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Department of Medical Oncology, The Christie NHS Foundation, Manchester, England, UK; Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Gianluca Masi
- Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy; Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Bruno Daniele
- Medical Oncology Unit, Ospedale del Mare, Napoli, Italy
| | - David James Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Andrea Casadei-Gardini
- Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Vita-Salute San Raffaele University, Milan, Italy; Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy
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12
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Chen W, Liu K, Wang Z, Zhang H, Tan M, Liu Y, Gao T, Su X, Gu L, Chen X, Cheng S. Migrasome-related ITGA5 for predicting prognosis, immune infiltration and drug sensitivity of hepatocellular carcinoma. Apoptosis 2025; 30:1424-1439. [PMID: 40146484 DOI: 10.1007/s10495-025-02103-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/15/2025] [Indexed: 03/28/2025]
Abstract
To clarify the biological functions and prognostic significance of migrasome-related integrin subunit alpha 5 (ITGA5) in hepatocellular carcinoma (HCC). We used The Cancer Genome Atlas datasets and RNA-seq data from nine sets of paired HCC and adjacent normal tissues to identify key migrasome-related genes through a comprehensive analysis and weighted correlation network analysis. We then confirmed their roles in HCC through analyses of gene mutations, methylation, and immune cell infiltration, as well as molecular docking, molecular dynamics, and cell experiments. A comprehensive analysis of migrasome-related genes showed that ITGA5 was a critical gene related to HCC, and it is highly expressed in HCC tissues, which is related to poor prognosis. Further enrichment analysis revealed that ITGA5 is involved in many pathways related to tumor occurrence and metastasis, such as the PI3K-AKT pathway. In addition, ITGA5 was found to be expressed in multiple types of immune cells and was closely associated with immune infiltration. Drug sensitivity, molecular docking, and molecular dynamics analyses indicated that ITGA5 may enhance the sensitivity of HCC to drug TGX221. Finally, cell phenotype experiments confirmed that ITGA5 knockdown suppressed the proliferation, migration, and invasion of HCC cells, and while overexpression exacerbated malignant phenotypes. Our analyses showed that ITGA5 is a key migrasome-related gene involved in the proliferation and metastasis of HCC that has promise as a therapeutic target and candidate prognostic indicator.
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Affiliation(s)
- Wanjin Chen
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China
- Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Kailin Liu
- Department of Endocrinology and Metabolism, The Fifth People's Hospital of Chongqing, Chongqing, 400062, China
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Chongqing University, Chongqing, 400062, China
| | - Zhiling Wang
- Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Hui Zhang
- Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Ming Tan
- Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Yuting Liu
- Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Tingting Gao
- Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Xiameng Su
- Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Leirong Gu
- Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Xinyan Chen
- Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Shengtao Cheng
- Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
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Lu Y, Lin J, Lu Y, Lin L, Zheng S, Chen Y, Huang S. Hepatotoxicity of ICI monotherapy or combination therapy in HCC: A systematic review and meta-analysis. PLoS One 2025; 20:e0323023. [PMID: 40440305 PMCID: PMC12121757 DOI: 10.1371/journal.pone.0323023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 04/01/2025] [Indexed: 06/02/2025] Open
Abstract
BACKGROUND The aim of this study was to reveal the hepatotoxicity profile of different immune checkpoint inhibitor (ICI) used strategies in patients with Hepatocellular carcinoma (HCC) by meta-analysis. METHODS Literature was searched through PubMed, Cochrane, Embase, and Web of Science up to October 14, 2023, and the subject terms were "Carcinoma, Hepatocellular" and "Immune Checkpoint Inhibitors". The main observations were alanine aminotransferase (ALT) and aspartate aminotransferase (AST). ALT and AST were graded according to CTCAE. RESULTS A total of 32 studies with 7662 patients were included in the analysis. The results of meta-analysis showed that among different ICI treatment regimens, ICI monotherapy had the lowest incidence of any grade of ALT and AST elevation, and the highest for ICI+multikinase inhibitor (MKI); ICI+anti-VEGFR/VEGFA and ICI monotherapy had a lower incidence of grade ≥3 ALT and AST elevations, while ICI + MKI, dual immunotherapy, and dual immunotherapy+MKI had a higher incidence of grade ≥3 ALT and AST elevations; ICI monotherapy was more prone to any grade ALT elevation than placebo, and ICI monotherapy was more prone to ≥ 3 grade AST elevation than MKI; combination immunotherapy was more prone than MKI to any grade ALT and AST elevations; in grade ≥3 ALT and AST elevations, combination immunotherapy was similar to ICI monotherapy and MKI; ICI + MKI was more likely to have grade ≥3 ALT. CONCLUSION ICI monotherapy was more likely to cause severe hepatotoxicity than MKI. Combination immunotherapy treatment increased the incidence of hepatotoxicity compared to monotherapy, and ICI + MKI was prone to develop severe hepatotoxicity.
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Affiliation(s)
- Yuping Lu
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian, PR China
| | - Jing Lin
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian, PR China
| | - Yufeng Lu
- School of Mathematics and Computer Science, Fuzhou University, Fujian, PR China
| | - Luping Lin
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian, PR China
| | - Shicheng Zheng
- School of Basic Medical Sciences, Fujian Medical University, Fujian, PR China
| | - Yu Chen
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian, PR China
| | - Sha Huang
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian, PR China
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14
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Mo PL, Lin M, Gao BW, Zhang SB, Chen JP. Knowledge structure analysis and network visualization of tumor-associated macrophages in hepatocellular carcinoma research: A bibliometric mapping. World J Clin Oncol 2025; 16:102747. [DOI: 10.5306/wjco.v16.i5.102747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/13/2025] [Accepted: 04/11/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) have demonstrated significant potential as a research and treatment approach for hepatocellular carcinoma (HCC). Nevertheless, a comprehensive quantitative analysis of TAMs in HCC remained insufficient. Therefore, the objective of this study was to employ bibliometric methods to investigate the development trends and research frontiers pertaining to this field.
AIM To determine the knowledge structure and current research hotspots by bibliometric analysis of scholarly papers pertaining to TAMs in HCC.
METHODS The present study employed the Web of Science Core Collection to identify all papers related to TAMs in HCC research. Utilizing the Analysis Platform of Bibliometrics, CiteSpace 6.2.R4, and Vosviewer 1.6.19, the study conducted a comprehensive analysis encompassing multiple dimensions such as publication quantity, countries of origin, affiliated institutions, publishing journals, contributing authors, co-references, author keywords, and emerging frontiers within this research domain.
RESULTS A thorough examination was undertaken on 818 papers within this particular field, published between January 1, 1985 to September 1, 2023, which has witnessed a substantial surge in scholarly contributions since 2012, with a notable outbreak in 2019. China was serving as the central hub in this field, with Fudan University leading in terms of publications and citations. Chinese scholars have taken the forefront in driving the research expansion within this field. Hepatology emerged as the most influential journal in this field. The study by Qian and Pollard in 2010 received the highest number of co-citations. It was observed that the citation bursts of references coincided with the outbreak of publications. Notably, “tumor microenvironment”, “immunotherapy”, “prognostic”, “inflammation”, and “polarization”, etc. emerged as frequently occurring keywords in this field. Of particular interest, “immune evasion”, “immune infiltration”, and “cancer genome atlas” were identified as emerging frontiers in recent research.
CONCLUSION The field of TAMs in HCC exhibited considerable potential, as evidenced by the promising prospects of immunotherapeutic interventions targeting TAMs for the amelioration of HCC. The emerging frontiers in this field primarily revolved around modulating the immunosuppressive characteristics of TAMs within a liver-specific immune environment, with a focus on how to counter immune evasion and reduce immune infiltration.
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Affiliation(s)
- Ping-Li Mo
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Ming Lin
- Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong Province, China
| | - Bo-Wen Gao
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
| | - Shang-Bin Zhang
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Jian-Ping Chen
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
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15
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Mahumud RA. Optimising Cancer Medicine in Clinical Practices: Are Neoadjuvant and Adjuvant Immunotherapies Affordable for Cancer Patients in Low- and Middle-Income Countries? Cancers (Basel) 2025; 17:1722. [PMID: 40427219 PMCID: PMC12109690 DOI: 10.3390/cancers17101722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Revised: 05/14/2025] [Accepted: 05/20/2025] [Indexed: 05/29/2025] Open
Abstract
Cancer immunotherapy, encompassing neoadjuvant and adjuvant interventions, has transformed treatment paradigms in multiple malignancies by leveraging the host immune system to combat tumour cells. While immunotherapies have demonstrated remarkable efficacy, particularly immune checkpoint inhibitors, high treatment costs undermine their accessibility and affordability in low- and middle-income countries (LMICs). This paper provides a prospective overview of the clinical benefits of neoadjuvant and adjuvant immunotherapies, examines the barriers to implementing these treatments in LMICs, and suggests potential strategies to improve equitable access. Such interventions necessitate a combined effort from healthcare providers, policymakers, and stakeholders to ensure their sustainable integration into global cancer care.
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Affiliation(s)
- Rashidul Alam Mahumud
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia; ; Tel.: +61-452457242
- School of Business, Faculty of Business, Education, Law and Arts, University of Southern Queensland, Toowoomba, QLD 4350, Australia
- Centre for Health Research, University of Southern Queensland, Toowoomba, QLD 4350, Australia
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16
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Xu L, Xiao T, Chao T, Xiong H, Yao W. From genes to therapy: a lipid Metabolism-Related genetic risk model predicts HCC outcomes and enhances immunotherapy. BMC Cancer 2025; 25:895. [PMID: 40389832 PMCID: PMC12090435 DOI: 10.1186/s12885-025-14306-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 05/09/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND Hepatocellular Carcinoma (HCC) is related to dysregulated lipid metabolism and immunosuppressive microenvironment. This study developed a genetic risk model using lipid metabolism-related genes to predict survival and immune patterns in HCC patients. METHODS Differentially expressed genes (DEGs) related to lipid metabolism were identified in HCC via the TCGA-LIHC dataset. A risk model for survival prediction was constructed via DEGs related to survival. The immune signature associated with the risk model was also evaluated by the CIBERSORT algorithm, tumor immune dysfunction and exclusion algorithm, and single sample gene set enrichment analysis. RESULTS This study identified six lipid metabolism-related genes, ADH4, LCAT, CYP2C9, CYP17A1, LPCAT1, and ACACA, to construct a lipid metabolism-related gene risk model that can divide HCC patients into low- and high-risk groups. Internal and external validation verified that the risk model could be a signature that could effectively predict HCC patient prognosis. High-risk patients showed disrupted immune cell profiles, reduced tumor-killing capacity, and increased expression of immune checkpoint genes. However, they responded more favorably to immune checkpoint inhibitor (ICB) therapy. The top ten hub genes related to the risk model were associated with tumor progression and deteriorating prognosis. In vitro experiments verified that the downregulation of the top 1 hub gene CDK1 was correlated to the HCC cell proliferation. CONCLUSION The risk model constructed using lipid metabolism-related genes could effectively predict prognosis and was related to the immunosuppressive microenvironment and ICB immunotherapy. The hub genes related to the risk model were potential therapeutic targets.
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Affiliation(s)
- Lei Xu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Ting Xiao
- Department of Ultrasonography, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Tengfei Chao
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Huihua Xiong
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
| | - Wei Yao
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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Jiang Y, Dong X, Zhang Y, Su F, Zhao L, Shi X, Zhong J. Navigating the complexities: challenges and opportunities in conversion therapy for advanced hepatocellular carcinoma. Clin Exp Med 2025; 25:169. [PMID: 40382739 PMCID: PMC12086121 DOI: 10.1007/s10238-025-01698-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Accepted: 04/14/2025] [Indexed: 05/20/2025]
Abstract
Primary liver cancer ranks as the sixth most prevalent malignant tumor and stands as the second leading cause of cancer-related mortality globally, posing a significant threat to public health. Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Surgical resection remains the cornerstone treatment for achieving radical cure and prolonged survival in HCC patients. Contrary to Western countries, the majority of HCC patients in China present with hepatitis B virus infection and consequent liver cirrhosis, with most cases diagnosed at an intermediate or advanced stage. This complexity results in a poor prognosis. Recent advancements in local therapeutic techniques and the introduction of systemic therapies, including targeted and immunotherapy agents, have provided new avenues for both clinical and basic conversion therapy for advanced HCC. Integrating multi-dimensional local and systemic therapies, multi-modal sequential, and comprehensive multidisciplinary approaches into the management of HCC patients has demonstrated promising conversion success rates. This holistic management strategy involves combining multiple treatment modalities vertically and coordinating various disciplines horizontally. However, significant challenges remain, including the precise selection of patients eligible for conversion therapy, the optimal choice of conversion therapy regimens, and the accurate determination of surgical timing post-conversion therapy. Addressing these challenges is crucial for hepatobiliary surgeons. High-quality, randomized controlled trials are urgently needed to generate robust evidence for clinical practice. This review aims to synthesize the latest research developments both in China and internationally and examines key issues in the realm of HCC conversion therapy.
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Affiliation(s)
- Yubo Jiang
- Department of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science, Jinan, Shandong Province, China
| | - Xiaofeng Dong
- Department of Hepatobiliary, Pancreas and Spleen Surgery, the People's Hospital of Guangxi Zhuang Autonomous Region (Guangxi Academy of Medical Sciences), Nanning, Guangxi Zhuang Autonomous Region, China
| | - Yingying Zhang
- Department of Oncology, Binzhou People's Hospital Affiliated to Shandong First Medical University, Binzhou, Shandong Province, China
| | - Feiyan Su
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Lei Zhao
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Xuetao Shi
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Jingtao Zhong
- Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
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Gill GS, Kharb S, Goyal G, Das P, Kurdia KC, Dhar R, Karmakar S. Immune Checkpoint Inhibitors and Immunosuppressive Tumor Microenvironment: Current Challenges and Strategies to Overcome Resistance. Immunopharmacol Immunotoxicol 2025:1-45. [PMID: 40376861 DOI: 10.1080/08923973.2025.2504906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 05/06/2025] [Indexed: 05/18/2025]
Abstract
Immune checkpoint inhibitors (ICIs) are shown to improve cancer treatment effectiveness by boosting the immune system of the patient. Nevertheless, the unique and highly suppressive TME poses a significant challenge, causing heterogeneity of response or resistance in a considerable number of patients. This review focuses on the evasive attributes of the TME. Immune evasion mechanism in TME include immunosuppressive cells, cytokine and chemokine signaling, metabolic alterations and overexpression of immune checkpoint molecules such as PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA and their interactions within the TME. In addition, this review focuses on the overcoming resistance by targeting immunosuppressive cells, normalizing tumor blood vessels, blocking two or three checkpoints simultaneously, combining vaccines, oncolytic viruses and metabolic inhibitors with ICIs or other therapies. This review also focuses on the necessity of finding predictive markers for the stratification of patients and to check response of ICIs treatment. It remains to be made certain by new research and intelligent innovations how these discoveries of the TME and its interplay facilitate ICI treatment and change the face of cancer treatment.
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Affiliation(s)
- Gurpreet Singh Gill
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Simmi Kharb
- Department of Biochemistry, Pt. B.D. Sharma Postgraduate Institute of Medical Sciences, Rohtak, India
| | - Gitanjali Goyal
- Department of Biochemistry, All India Institute of Medical Sciences, Bathinda, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Kailash Chand Kurdia
- Department of GI Surgery & Liver Transplantation, All India Institute of Medical Sciences, New Delhi, India
| | - Ruby Dhar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Subhradip Karmakar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
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19
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Xiao Q, Liu Y, Li T, Wang C, He S, Zhai L, Yang Z, Zhang X, Wu Y, Liu Y. Viral oncogenesis in cancer: from mechanisms to therapeutics. Signal Transduct Target Ther 2025; 10:151. [PMID: 40350456 PMCID: PMC12066790 DOI: 10.1038/s41392-025-02197-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 01/22/2025] [Accepted: 03/03/2025] [Indexed: 05/14/2025] Open
Abstract
The year 2024 marks the 60th anniversary of the discovery of the Epstein-Barr virus (EBV), the first virus confirmed to cause human cancer. Viral infections significantly contribute to the global cancer burden, with seven known Group 1 oncogenic viruses, including hepatitis B virus (HBV), human papillomavirus (HPV), EBV, Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human immunodeficiency virus (HIV). These oncogenic viruses induce cellular transformation and cancer development by altering various biological processes within host cells, particularly under immunosuppression or co-carcinogenic exposures. These viruses are primarily associated with hepatocellular carcinoma, gastric cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi sarcoma, lymphoma, and adult T-cell leukemia/lymphoma. Understanding the mechanisms of viral oncogenesis is crucial for identifying and characterizing the early biological processes of virus-related cancers, providing new targets and strategies for treatment or prevention. This review first outlines the global epidemiology of virus-related tumors, milestone events in research, and the process by which oncogenic viruses infect target cells. It then focuses on the molecular mechanisms by which these viruses induce tumors directly or indirectly, including the regulation of oncogenes or tumor suppressor genes, induction of genomic instability, disruption of regular life cycle of cells, immune suppression, chronic inflammation, and inducing angiogenesis. Finally, current therapeutic strategies for virus-related tumors and recent advances in preclinical and clinical research are discussed.
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Affiliation(s)
- Qing Xiao
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yi Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Tingting Li
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Chaoyu Wang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Sanxiu He
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Liuyue Zhai
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Zailin Yang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Xiaomei Zhang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yongzhong Wu
- Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yao Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
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20
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Gu J, Bao S, Han L, Yu X, Jia Z, Huang C. Prediction of PD-1 Expression and Outcomes of Combined Therapy in Hepatocellular Carcinoma: an MRI-Based Radiomics Approach. JOURNAL OF IMAGING INFORMATICS IN MEDICINE 2025:10.1007/s10278-024-01381-7. [PMID: 40355688 DOI: 10.1007/s10278-024-01381-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 11/28/2024] [Accepted: 12/09/2024] [Indexed: 05/14/2025]
Abstract
This study aims to assess the value of clinical and MRI radiomics features in noninvasively predicting programmed cell death protein 1 (PD-1) expression level and the response to anti-PD-1 immunotherapy combined with transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). A total of 107 HCC patients (85 in training set and 22 in validation set) with PD-1 positive (n = 41) and negative (n = 66) were enrolled. Radiomics features were extracted from T2-weighted, fat suppression T2-weighted, contrast-enhanced, and diffusion-weighted images. A clinical model was constructed based on independent clinical risk factors (p < 0.05), while a radiomics model was developed utilizing the optimal radiomics signature. A radiomics nomogram model for predicting PD-1 integrated the significant clinical and radiomics features. The performance of nomogram was evaluated with respect to its discrimination and clinical utility and compared with that of clinical and radiomics prediction models. The radiomics nomogram, combining the clinical factors with the Rad-score, had best prediction performance (area under the curve [AUC]: 0.95 in the training set; AUC: 0.86 in the validation set). Decision curve analysis (DCA) showed that the nomogram exhibited superior accuracy in clinical assessment compared to the other models. The predicted high-risk group of PD-1 had longer overall survival (OS) than the predicted low-risk group after receiving anti-PD-1 therapy combined with TACE. The MRI-based radiomics nomogram performed well for identifying high-risk PD-1 group for combination therapy and may inform personalized treatment decision-making strategies.
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Affiliation(s)
- Jingxiao Gu
- Research Centre of Molecular Medicine, Nantong Health College of Jiangsu Province, Nantong, 226001, The People's Republic of China
- Department of Vascular Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, The People's Republic of China
| | - Shanlei Bao
- Department of Nuclear Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Lu Han
- Philips Healthcare, Shanghai, China
| | - Xiao Yu
- Philips Healthcare, Shanghai, China
| | - Zhongzheng Jia
- Department of Radiology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China.
| | - Chen Huang
- Department of Vascular Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, The People's Republic of China.
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21
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Lin JW, Zhang S, Shen J, Yin Y, Yang J, Ni CF, Wang WS. The efficacy of transarterial chemoembolization combined with helical iodine-125 seed implant, lenvatinib and PD-1 inhibitors in patients with hepatocellular carcinoma complicated by main portal vein tumor thrombus: a retrospective study. Front Oncol 2025; 15:1514375. [PMID: 40406260 PMCID: PMC12094993 DOI: 10.3389/fonc.2025.1514375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 04/09/2025] [Indexed: 05/26/2025] Open
Abstract
Purpose To evaluate the efficacy and safety of a multimodal therapeutic approach involving transarterial chemoembolization (TACE) in conjunction with helical iodine-125 (I-125) seed implant, lenvatinib, and programmed cell death-1(PD-1) inhibitors for hepatocellular carcinoma (HCC) complicated by main portal vein tumor thrombus (MPVTT). Material and methods HCC patients with MPVTT treated with TACE coupled with helical I-125 implant, lenvatinib, PD-1 inhibitors between September 2019 and August 2022 were retrospectively analyzed, and constituted as study group. Those treated with TACE, helical I-125 seed implant, and sorafenib between December 2016 and August 2020 served as the historical control group. All patients received sorafenib or lenvatinib combined with PD-1 inhibitors within 3-7 days after TACE and helical I-125 seed implantation. The longest follow-up period for all patients in both groups was 36 months from the date of helical I-125 seed implantation. Primary outcome was overall survival time (OS), and secondary outcomes were progression free survival time (PFS), objective response rate (ORR), and disease control rate (DCR). The Cox proportional hazards regression model was employed to identify independent prognostic factors influencing OS and PFS. The value P < 0.05 was deemed statistically significant. Results A total of 53 patients were enrolled, with 22 assigned to the study group and 31 to the control group. The study group exhibited superior overall ORR(54.5% vs. 25.8%, P = 0.033) and overall DCR (77.3% vs. 64.5%, P = 0.319). Notably, the ORR and DCR of MPVTT were higher in the study group (86.4% vs. 51.6%, P = 0.008; and 95.5% vs. 83.9%, P = 0.382, respectively). Median OS (16.1 ± 6.1 months vs. 10.2 ± 0.8 months, P = 0.008) and PFS (13.6 ± 3.0 months vs. 6.1 ± 0.6 months, P = 0.014) were prolonged in the study group. The maximal tumor size, alpha fetoprotein level, and treatment modality were independent predictors for OS, while the maximal tumor size and treatment modality were independent determinants for PFS. Study group showed frequent hypothyroidism and reactive cutaneouscapillary (P < 0.01), with comparable grade 3/4 adverse events between groups. Conclusions The integration of the helical I-125 seed implant with TACE, lenvatinib, and PD-1 inhibitors is the safe and efficacious approach in the management of HCC complicated by MPVTT.
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Affiliation(s)
- Jia-Wen Lin
- Department of International Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Department of International Radiology, Zhongshan People’s Hospital, Zhongshan, China
| | - Shen Zhang
- Department of International Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jian Shen
- Department of International Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yu Yin
- Department of International Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jun Yang
- Department of International Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Cai-Fang Ni
- Department of International Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wan-Sheng Wang
- Department of International Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Department of International Radiology, The First People’s Hosiptal of Kunshan, Suzhou, China
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22
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Wang Q, Yuan F, Zuo X, Li M. Breakthroughs and challenges of organoid models for assessing cancer immunotherapy: a cutting-edge tool for advancing personalised treatments. Cell Death Discov 2025; 11:222. [PMID: 40335487 PMCID: PMC12059183 DOI: 10.1038/s41420-025-02505-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 04/16/2025] [Accepted: 04/23/2025] [Indexed: 05/09/2025] Open
Abstract
Organoid models are powerful tools for evaluating cancer immunotherapy that provide a more accurate representation of the tumour microenvironment (TME) and immune responses than traditional models. This review focuses on the latest advancements in organoid technologies, including immune cell co-culture, 3D bioprinting, and microfluidic systems, which enhance the modelling of TME and facilitate the assessment of immune therapies such as immune checkpoint inhibitors (ICIs), CAR-T therapies, and oncolytic viruses. Although these models have great potential in personalised cancer treatment, challenges persist in immune cell diversity, long-term culture stability, and reproducibility. Future developments integrating artificial intelligence (AI), multi-omics, and high-throughput platforms are expected to improve the predictive power of organoid models and accelerate the clinical translation of immunotherapy.
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Affiliation(s)
- Qian Wang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210009, Jiangsu, PR China
- The Fourth Clinical College of Nanjing Medical University, Nanjing, 210009, Jiangsu, PR China
| | - Fangwei Yuan
- Department of Thoracic Surgery, Lian Shui County People's Hospital, Huaian, 223400, Jiangsu, PR China
| | - Xianglin Zuo
- Biobank of Jiangsu Cancer Hospital (Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University), Nanjing, 210000, Jiangsu, PR China.
| | - Ming Li
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210009, Jiangsu, PR China.
- The Fourth Clinical College of Nanjing Medical University, Nanjing, 210009, Jiangsu, PR China.
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23
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Chu X, Pu N, Yang X, Xie Y, Liu L, Jin Y. Subtypes of tumor-associated neutrophils and their roles in cancer immunotherapy. Crit Rev Oncol Hematol 2025; 212:104763. [PMID: 40334802 DOI: 10.1016/j.critrevonc.2025.104763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/30/2025] [Accepted: 05/02/2025] [Indexed: 05/09/2025] Open
Abstract
Neutrophils are essential components of the innate immune system. Tumor-associated neutrophils (TANs) are shaped by tumor microenvironment (TME), leading to significant heterogeneity in biological characteristics and functions. Recent advances in single-cell sequencing have revealed a wide array of TAN subtypes, while a comprehensive classification system is still lacking. This review aims to summarize the alterations observed in TAN subgroups following cancer immunotherapy, and identify the distinctions and commonalities between pro-tumor and anti-tumor subgroups. Current progress of preclinical and clinical studies is also highlighted, involving novel therapies targeting TANs.
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Affiliation(s)
- Xinyun Chu
- Department of Hepatobiliary & Pancreatic Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650000, China; Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Ning Pu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xue Yang
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yuqi Xie
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liang Liu
- Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Yun Jin
- Department of Hepatobiliary & Pancreatic Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650000, China.
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24
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Ying S, Liu H, Zhang Y, Mei Y. Harnessing Dendritic Cell Function in Hepatocellular Carcinoma: Advances in Immunotherapy and Therapeutic Strategies. Vaccines (Basel) 2025; 13:496. [PMID: 40432108 PMCID: PMC12115466 DOI: 10.3390/vaccines13050496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/29/2025] [Accepted: 05/01/2025] [Indexed: 05/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Conventional therapies are frequently limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Dendritic cells (DCs), central to orchestrating antitumor immunity, have become key targets for HCC immunotherapy. This review examines the biological functions of DC subsets (cDC1, cDC2, pDC, and moDC) and their roles in initiating and modulating immune responses against HCC. We detail the mechanisms underlying DC impairment within the TME, including suppression by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). Additionally, we discuss novel DC-based therapeutic strategies, such as DC-based vaccines designed to enhance antigen presentation and T cell activation. Combining DC vaccines with immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 and CTLA-4 blockers, demonstrates synergistic effects that can overcome immune evasion and improve clinical outcomes. Despite progress, challenges related to DC subset heterogeneity, TME complexity, and patient variability require the further optimization and personalization of DC-based therapies. Future research should focus on refining these strategies, leveraging advanced technologies like genomic profiling and artificial intelligence, to maximize therapeutic efficacy and revolutionize HCC treatment. By restoring DC function and reprogramming the TME, DC-based immunotherapy holds immense potential to transform the management of HCC and improve patient survival.
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Affiliation(s)
- Shiding Ying
- Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China;
| | - Haiyan Liu
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore;
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore 117456, Singapore
| | - Yongliang Zhang
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore;
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore 117456, Singapore
| | - Yu Mei
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore;
- NUSMED Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
- Immunology Programme, Life Science Institute, National University of Singapore, Singapore 117456, Singapore
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25
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Jiang K, Liu M, Zhao X, Wang S, Ling Y, Qiao L, Tu J, Peng Z. Evaluation of surrogate endpoints in phase III randomized control trials of advanced hepatocellular carcinoma treated with immune checkpoint inhibitors. Eur J Clin Pharmacol 2025; 81:727-737. [PMID: 40080137 DOI: 10.1007/s00228-025-03820-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 02/28/2025] [Indexed: 03/15/2025]
Abstract
PURPOSE Overall survival (OS) is recommended as a gold standard endpoint but has some limitations. We aimed to finding more effective surrogate endpoints for advanced hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs). METHODS Three online databases were searched for randomized control trials (RCTs) on HCC, published between January 2015 and July 2023, that evaluated ICIs and reported progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and OS. The correlation between the potential surrogate endpoints and OS was evaluated at the trial, arm, and patient levels. The prediction models were validated in single-arm or non-RCTs. Individual data were collected from a real-world (RW) cohort with advanced HCC underwent ICI monotherapy at three tertiary medical centers in China. RESULTS Ten RCTs (6023 participants) with 11 comparisons were included. PFS had a moderately significant association with OS (R2 = 0.50, p = 0.014). ORR, DCR, and OS showed weak correlations. On limiting the analysis to ICI monotherapy studies, the correlations of OS with PFS became stronger (R2 = 0.85, p = 0.02). The RW cohort also verified that PFS was closely related to OS when patient received with ICI monotherapy. CONCLUSION PFS are recommended as surrogate markers in patients with advanced HCC treated with ICI monotherapy.
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Affiliation(s)
- Ke Jiang
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2Nd Rd, Guangzhou, 510080, China
- Cancer Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Miaowen Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2Nd Rd, Guangzhou, 510080, China
- Cancer Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiao Zhao
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2Nd Rd, Guangzhou, 510080, China
- Cancer Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Shutong Wang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yunyan Ling
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2Nd Rd, Guangzhou, 510080, China
- Cancer Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China
| | - Liangliang Qiao
- Department of Interventional Oncology, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Jianfei Tu
- Cancer Center, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China.
| | - Zhenwei Peng
- Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan 2Nd Rd, Guangzhou, 510080, China.
- Cancer Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.
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Rao S, Prince SP, Gaddipati S, Feun L, Ezenwajiaku N, Martin P, Jones PD. Looking Toward the Future: Emerging Therapies for Hepatocellular Carcinoma. Gastroenterol Hepatol (N Y) 2025; 21:286-297. [PMID: 40416920 PMCID: PMC12100529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2025]
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide. Despite the decreasing prevalence of hepatitis C, the burden of HCC is expected to rise owing to the increasing prevalence of metabolic syndrome and increased global alcohol consumption. Guideline-concordant screening with ultrasound every 6 months has been associated with increased rates of early-stage detection and receipt of curative treatment. However, most patients with cirrhosis do not undergo screening, with HCC often diagnosed only at an advanced stage when curative resection or ablation is not feasible. Systemic medical therapy is indicated in patients diagnosed with infiltrative or advanced HCC, or when early-stage disease progresses or recurs after resection, transplant, or other locoregional therapy. Sorafenib was approved as first-line therapy for HCC in 2007. Since 2017, there has been an exponential rate of approval of novel agents targeting HCC, including lenvatinib, regorafenib, and cabozantinib. Checkpoint inhibitors, including pembrolizumab, nivolumab, ipilimumab, and combination therapy with atezolizumab plus bevacizumab and durvalumab plus tremelimumab, have expanded treatment options. This article describes treatment for all HCC stages, with a brief discussion of locoregional therapy for context, as some emerging treatment regimens combine locoregional and systemic therapies. The article highlights approved systemic therapies that are guideline-endorsed and emerging therapies for advanced HCC.
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Affiliation(s)
- Sanjana Rao
- University of Miami/Jackson Health System Internal Medicine Residency, University of Miami Miller School of Medicine, Miami, Florida
| | - Sean-Patrick Prince
- University of Miami/Holy Cross Health Internal Medicine Program, Fort Lauderdale, Florida
| | - Sirisha Gaddipati
- University of Miami/Jackson Health System Internal Medicine Residency, University of Miami Miller School of Medicine, Miami, Florida
| | - Lynn Feun
- Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Miami, Florida
| | - Nkiruka Ezenwajiaku
- Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Miami, Florida
| | - Paul Martin
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida
| | - Patricia D. Jones
- Department of Medicine, Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
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27
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Vogel A, Chan SL, Dawson LA, Kelley RK, Llovet JM, Meyer T, Ricke J, Rimassa L, Sapisochin G, Vilgrain V, Zucman-Rossi J, Ducreux M. Hepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2025; 36:491-506. [PMID: 39986353 DOI: 10.1016/j.annonc.2025.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 02/10/2025] [Accepted: 02/11/2025] [Indexed: 02/24/2025] Open
Affiliation(s)
- A Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Division of Hepatology, Toronto General Hospital, Toronto, Canada; Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada
| | - S L Chan
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - L A Dawson
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada
| | - R K Kelley
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA
| | - J M Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA; Liver Cancer Translational Research Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - T Meyer
- Department of Oncology, Royal Free Hospital, London, UK; UCL Cancer Institute, University College London, London, UK
| | - J Ricke
- Klinik und Poliklinik für Radiologie, Ludwig-Maximilians-Universität München, Munich, Germany
| | - L Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - G Sapisochin
- Department of Surgery, University of Toronto, Toronto, Canada
| | - V Vilgrain
- Centre de Recherche sur l'Inflammation U 1149, Université Paris Cité, Paris, France; Department of Radiology, Beaujon Hospital, APHP Nord, Clichy, France
| | - J Zucman-Rossi
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, INSERM, Paris, France
| | - M Ducreux
- INSERM U1279, Université Paris-Saclay, Villejuif, France; Department of Cancer Medicine, Gustave Roussy, Villejuif, France
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28
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Wang P, Qiu J, Fang Y, Li S, Liu K, Cao Y, Zhang G, Wang Z, Gu X, Wu J, Jiang C. SENP3 inhibition suppresses hepatocellular carcinoma progression and improves the efficacy of anti-PD-1 immunotherapy. Cell Death Differ 2025; 32:959-972. [PMID: 39755756 PMCID: PMC12089275 DOI: 10.1038/s41418-024-01437-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 12/08/2024] [Accepted: 12/16/2024] [Indexed: 01/06/2025] Open
Abstract
The importance of SUMOylation in tumorigenesis has received increasing attention, and research on therapeutic agents targeting this pathway has progressed. However, the potential function of SUMOylation during hepatocellular carcinoma (HCC) progression and the underlying molecular mechanisms remain unclear. Here, we identified that SUMO-Specific Peptidase 3 (SENP3) was upregulated in HCC tissues and correlated with a poor prognosis. Multiple functional experiments demonstrated that SENP3 promotes the malignant phenotype of HCC cells. Mechanistically, SENP3 deSUMOylates RACK1 and subsequently increases its stability and interaction with PKCβII, thereby promoting eIF4E phosphorylation and translation of oncogenes, including Bcl2, Snail and Cyclin D1. Additionally, tumor-intrinsic SENP3 promotes the infiltration of tumor-associated macrophages (TAMs) while reducing cytotoxic T cells to facilitate immune evasion. Mechanistically, SENP3 promotes translation of CCL20 via the RACK1 /eIF4E axis. Liver-specific knockdown of SENP3 significantly inhibits liver tumorigenesis in a chemically induced HCC model. SENP3 inhibition enhances the therapeutic efficacy of PD-1 blockade in an HCC mouse model. Collectively, SENP3 plays cell-intrinsic and cell-extrinsic roles in HCC progression and immune evasion by modulating oncogene and cytokine translation. Targeting SENP3 is a novel therapeutic target for boosting HCC responsiveness to immunotherapy.
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Affiliation(s)
- Peng Wang
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
- State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China
| | - Jiannan Qiu
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
| | - Yuan Fang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Songmao Li
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease,, Nanjing Medical University, Nanjing, China
| | - Kua Liu
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
- State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China
| | - Yin Cao
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Guang Zhang
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zhongxia Wang
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Xiaosong Gu
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
| | - Junhua Wu
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
- State Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.
| | - Chunping Jiang
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
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Chai J, Li L, Wu Q, Zhang S. CD96: immunoregulation and its role and prospect in immunotherapy of primary hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2025; 37:534-539. [PMID: 39976070 DOI: 10.1097/meg.0000000000002916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Recently, immune checkpoint inhibitors have been widely used in the treatment of advanced liver cancer. Immune checkpoints are a type of molecules that play an important role in the self-regulation of the immune system. In tumor immunity, their activation by immune checkpoints leads to the inhibition of effector lymphocyte activation or the mediation of cytotoxic T cell dysfunction, resulting in immune escape. These immune checkpoints include programmed death receptor 1 (PD-1) and its ligand PD-L1, as well as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and others. Immune checkpoint inhibitors block the interaction between immune checkpoint receptors and ligands, thereby relieving the immune suppression caused by immune checkpoints, and reactivating immune cells to exert antitumor effects. With the continuous progress of immunotherapy research, drugs targeting PDL-1, PD-1, and CTLA-4 have played an important role in clinical treatment. However, some patients still cannot benefit from immunotherapy; therefore, multitarget immunotherapy is an important way to improve the response rate of immunotherapy. CD96 is one of the members of the immunoglobulin superfamily receptors, which mainly functions by regulating natural killer cells and CD8+ T cells, and is expected to become a new generation of immune checkpoints. This article reviews the molecular structure of CD96, its role in tumor immunity, and its application in hepatocellular carcinoma, hoping to provide reference for related research.
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Affiliation(s)
- Jiaqi Chai
- Department of Colorectal Surgery, 731 Hospital of China Aerospace Science and Industry Group
| | - Luyang Li
- Department of Hepatobiliary Surgery, Air Force Medical Center, Air Force Medical University Beijing
| | - Qimei Wu
- Graduate School of China Medical University, Shenyang, China
| | - Shuhan Zhang
- Department of Hepatobiliary Surgery, Air Force Medical Center, Air Force Medical University Beijing
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30
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Wang J, Chen Q, Shan Q, Liang T, Forde P, Zheng L. Clinical development of immuno-oncology therapeutics. Cancer Lett 2025; 617:217616. [PMID: 40054657 PMCID: PMC11930610 DOI: 10.1016/j.canlet.2025.217616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025]
Abstract
Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.
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Affiliation(s)
- Jianxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qi Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qiang Shan
- Department of General Surgery, Haining People's Hospital, Haining, 314400, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Patrick Forde
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
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31
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Liang C, Ye M, Yu L, Zhang P, Guo X, Meng X, Zeng H, Hu S, Zhang D, Sun Q, Shen Y, Cai J, Li S, Chen Z, Shi Y, Ke A, Shi YG, Zhou J, Fan J, Wu F, Huang X, Shi G, Tang Z, Lu J. Lysine-specific demethylase 1 deletion reshapes tumour microenvironment to overcome acquired resistance to anti-programmed death 1 therapy in liver cancer. Clin Transl Med 2025; 15:e70335. [PMID: 40356247 PMCID: PMC12069797 DOI: 10.1002/ctm2.70335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 04/24/2025] [Accepted: 04/28/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Immune checkpoint blockade, particularly targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), shows promise in treating hepatocellular carcinoma (HCC). However, acquired resistance, especially in patients with 'hot tumours', limits sustained benefits. Lysine-specific demethylase 1 (LSD1) plays a role in converting 'cold tumours' to 'hot tumours', but its involvement in PD-1 inhibitor resistance in HCC is unclear. METHODS LSD1 and PD-L1 expression, along with CD8+ T cell infiltration, were assessed using immunohistochemistry in HCC tissues, correlating these markers with patient prognosis. The impact of LSD1 deletion on tumour cell proliferation and CD8+ T cell interactions was examined in vitro. Mouse models were used to study the combined effects of LSD1 inhibition and anti-PD-1 therapy on tumour growth and the tumour microenvironment (TME). The clinical relevance of LSD1, CD74 and effector CD8+ T cells was validated in advanced HCC patients treated with PD-1 blockade. RESULTS LSD1 overexpression in HCC patients correlated with reduced PD-L1 expression, less CD8+ T cell infiltration and poorer prognosis. LSD1 deletion increased PD-L1 expression, boosted effector CD8+ T cells in vitro and inhibited tumour growth in vivo. While anti-PD-1 monotherapy initially suppressed tumour growth, it led to relapse upon antibody withdrawal. In contrast, combining LSD1 inhibition with anti-PD-1 therapy effectively halted tumour growth and prevented relapse, likely through TME remodelling, enhanced CD8+ T cell activity and improved CD74-mediated antigen presentation. Clinically, low LSD1 expression was associated with better response to anti-PD-1 therapy. CONCLUSION LSD1 deletion reshapes the TME, enhances CD8+ T cell function and prevents acquired resistance to anti-PD-1 therapy in HCC. The combination of LSD1 inhibitors and PD-1 blockade offers a promising strategy for overcoming resistance in advanced HCC. KEY POINTS Uncovering the synthetic lethality resulting from LSD1 deletion and PD1 inhibitor co-administration, evaluating their combined effects on tumour growth and TME remodelling. Elucidating the mechanism underlying the combined therapy of LSD1 deletion with PD1 inhibition for HCC. Exploring the implications of LSD1, CD74 and effector CD8+ T cell expression levels in advanced HCC patients undergoing anti-PD1 treatment.
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Affiliation(s)
- Chen Liang
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Mu Ye
- Shanghai Institute of Infectious Disease and BiosecurityFudan UniversityShanghaiChina
| | - Lei Yu
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of ChinaShanghaiChina
| | - Peng‐Fei Zhang
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
- Department of Medical OncologyShanghai Geriatric Medical Center (Zhongshan Hospital, Fudan University Minhang Meilong)ShanghaiChina
| | - Xiao‐Jun Guo
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Xian‐Long Meng
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Hai‐Ying Zeng
- Department of PathologyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Shu‐Yang Hu
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Dao‐Han Zhang
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Qi‐Man Sun
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Ying‐Hao Shen
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Jia‐Bin Cai
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Shuang‐Qi Li
- Key Laboratory of Medical Epigenetics and MetabolismInstitutes of Biomedical SciencesFudan UniversityShanghaiChina
| | - Zhen Chen
- Clinical Research Unit, Institute of Clinical ScienceZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Ying‐Hong Shi
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Ai‐Wu Ke
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Yujiang G. Shi
- Key Laboratory of Medical Epigenetics and MetabolismInstitutes of Biomedical SciencesFudan UniversityShanghaiChina
| | - Jian Zhou
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of ChinaShanghaiChina
| | - Jia Fan
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Fei‐Zhen Wu
- Key Laboratory of Medical Epigenetics and MetabolismInstitutes of Biomedical SciencesFudan UniversityShanghaiChina
| | - Xiao‐Yong Huang
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education of the People's Republic of ChinaShanghaiChina
| | - Guo‐Ming Shi
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
- Shanghai Institute of Infectious Disease and BiosecurityFudan UniversityShanghaiChina
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
- Clinical Research Unit, Institute of Clinical ScienceZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Zheng Tang
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Jia‐Cheng Lu
- Department of Liver Surgery and TransplantationZhongshan Hospital, Fudan UniversityShanghaiChina
- Liver Cancer InstituteZhongshan Hospital, Fudan UniversityShanghaiChina
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Miri H, Rahimzadeh P, Hashemi M, Nabavi N, Aref AR, Daneshi S, Razzaghi A, Abedi M, Tahmasebi S, Farahani N, Taheriazam A. Harnessing immunotherapy for hepatocellular carcinoma: Principles and emerging promises. Pathol Res Pract 2025; 269:155928. [PMID: 40184729 DOI: 10.1016/j.prp.2025.155928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 03/12/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025]
Abstract
HCC is considered as one of the leadin causes of death worldwide, with the ability of resistance towards therapeutics. Immunotherapy, particularly ICIs, have provided siginficant insights towards harnessing the immune system. The present review introduces the concepts and possibilities of immunotherapy for HCC treatment, emphasizing its underlying mechanisms and capacity to enhance patient results, focusing on both pre-clinical and clinical insights. The functions of TME and immune evasion mechanisms typical of HCC would be evaluated along with how contemporary immunotherapeutic approaches are designed to address these challenges. Furthermore, the clinical application of immunotherapy in HCC is discussed, emphasizing recent trial findings demonstrating the effectiveness and safety of drugs. In addition, the problems caused by immune evasion and resistance would be discussed to increase potential of immunotherapy along with combination therapy.
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Affiliation(s)
- Hossein Miri
- Faculty of Medicine, Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University Of Medical Sciences, Jiroft, Iran
| | - Alireza Razzaghi
- Social Determinants of Health Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Abedi
- Department of Pathology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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33
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Lai G, Xie B, Zhang C, Zhong X, Deng J, Li K, Liu H, Zhang Y, Liu A, Liu Y, Fan J, Zhou T, Wang W, Huang A. Comprehensive analysis of immune subtype characterization on identification of potential cells and drugs to predict response to immune checkpoint inhibitors for hepatocellular carcinoma. Genes Dis 2025; 12:101471. [PMID: 40092490 PMCID: PMC11907441 DOI: 10.1016/j.gendis.2024.101471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 04/12/2024] [Accepted: 11/02/2024] [Indexed: 03/19/2025] Open
Abstract
Immunosubtyping enables the segregation of immune responders from non-responders. However, numerous studies failed to focus on the integration of cellular heterogeneity and immunophenotyping in the prediction of hepatocellular carcinoma (HCC) patients' response to immune checkpoint inhibitors (ICIs). We categorized HCC patients into various immune subtypes based on feature scores linked to ICI response. Single-cell sequencing technology was to investigate the cellular heterogeneity of different immune subtypes and acquire significant ICI response-associated cells. Candidate drugs were identified using a blend of various drug databases and network approaches. HCC patients were divided into two distinct immune subtypes based on characterization scores of 151 immune-related gene sets. Patients in both subtypes showed varying overall survival, immunity levels, biological activities, and TP53 mutation rates. Subtype 1-related natural killer cells showed a positive correlation with immune-promoting scores but a negative correlation with immune-suppressing scores. Notably, docetaxel sensitivity in HCC patients rose as the levels of subtype 1-related natural killer cells increased. Our study demonstrated that immune subtypes have cellular heterogeneity in predicting response to ICIs. A combination of subtype 1-associated natural killer cells and docetaxel may offer new hope for ICI treatment in HCC.
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Affiliation(s)
- Guichuan Lai
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Biao Xie
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Cong Zhang
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Xiaoni Zhong
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Jielian Deng
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Kangjie Li
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Hui Liu
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Yuan Zhang
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Anbin Liu
- Department of Applied Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Yi Liu
- Department of Applied Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Jie Fan
- Department of Epidemiology, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Tianyi Zhou
- Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Wei Wang
- Department of Applied Statistics, School of Public Health, Chongqing Medical University, Chongqing 401331, China
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China
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34
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Dobrosotskaya IY, Kumar R, Frankel TL. Role of Immunotherapy in the Treatment of Hepatocellular Carcinoma. Curr Oncol 2025; 32:264. [PMID: 40422523 DOI: 10.3390/curroncol32050264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/25/2025] [Accepted: 04/29/2025] [Indexed: 05/28/2025] Open
Abstract
Hepatocellular carcinoma is the most common primary liver tumor and is strongly related to underlying liver cirrhosis. Common etiologies include viral hepatitis, elevated alcohol consumption and metabolic diseases, all of which result in liver inflammation and scarring. Previously, systemic therapies for locally advanced or metastatic disease were limited to tyrosine kinase inhibitors with poor efficacy and rare cures. Recent advances have harnessed the power of the immune system to combat disease, resulting in improved outcomes and occasional cures. Here, we describe the recent clinical trials in immunotherapies for the treatment of hepatocellular carcinoma as first- and second-line therapies and in combination with other drug classes.
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Affiliation(s)
- Irina Y Dobrosotskaya
- Section of Medical Oncology, Department of Medicine, Ann Arbor Veterans Healthcare System, Ann Arbor, MI 48105, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rashmi Kumar
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
| | - Timothy L Frankel
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
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Zhang Z, Zhao T, Meng W, Chen J, He C, Sun X, Huang H. DNA methylation-driven genes in hepatocellular carcinoma patients: insights into immune infiltration and prognostic implications. Front Med (Lausanne) 2025; 12:1520380. [PMID: 40357287 PMCID: PMC12066630 DOI: 10.3389/fmed.2025.1520380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 04/09/2025] [Indexed: 05/15/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) poses a significant global burden as a highly prevalent and life-threatening malignant tumor that endangers human life and wellbeing. The purpose of this study was to examine how DNA methylation-driven genes impact the prognosis of HCC patients. Methods Differentially expressed genes from The Cancer Genome Atlas, GSE76427, GSE25097 and GSE14520 datasets were collected to perform differential expression analysis between HCC patients and controls. Weighted gene coexpression network analysis (WGCNA) was subsequently performed to create coexpression modules for the DEGs. Then, ssGSEA was employed to investigate the infiltration of immune cells in HCC. Enrichment analysis and methylation were carried out for the module genes. We utilized Kaplan-Meier survival analysis to assess patient prognosis. Results Eight coexpression modules were identified via WGCNA for 1927 upregulated and 1,231 downregulated DEGs, after which the hub genes of the modules were identified. Module 5 had high immune infiltration, and the hub gene SCAMP3 was positively associated with Tcm. Module 3 exhibited a low level of immune infiltration, and the expression of the hub gene HCLS1 was negatively correlated with T cells and dendritic cells. Furthermore, we obtained five hub genes (BOP1, BUB1B, NOTCH3, SCAMP3, and SNRPD2) as methylation-driven genes. BOP1 and BUB1B were found to be correlated with unfavorable overall survival in patients with HCC. Conclusion HCLS1 and SCAMP3 are associated with immunity, whereas BOP1 and BUB1B are modified by methylation and may serve as prognostic markers for HCC.
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Affiliation(s)
- Zhi Zhang
- Department of Hepatobiliary Surger, Guangxi Medical University Affliated Wuming Hospital, Nanning, China
| | - Tongling Zhao
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, China
| | - Weida Meng
- Department of Hepatobiliary Surger, Guangxi Medical University Affliated Wuming Hospital, Nanning, China
| | - Jiahao Chen
- Department of Hepatobiliary Surger, Guangxi Medical University Affliated Wuming Hospital, Nanning, China
| | - Chengyi He
- Department of Hepatobiliary Surger, Guangxi Medical University Affliated Wuming Hospital, Nanning, China
| | - Xing Sun
- Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hai Huang
- Department of Hepatobiliary Surger, Guangxi Medical University Affliated Wuming Hospital, Nanning, China
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Xiong K, Huang K, Liu Y, Pang H, Chen P, Zheng Y, Li T, Li Z, Zhang M, Zheng D, Huang X, Cao M, Li Q, Liang J, Fan H, Li D, Sun J, Wen Z, Jiang Y. Efficacy and safety of TACE combined with TKIs and PD-1 inhibitors in HCC patients with prior TIPS. Front Oncol 2025; 15:1570029. [PMID: 40342829 PMCID: PMC12058502 DOI: 10.3389/fonc.2025.1570029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Accepted: 03/31/2025] [Indexed: 05/11/2025] Open
Abstract
Purpose To compare the efficacy and safety of TACE combined with TKIs and PD-1 inhibitors between HCC patients with and without prior TIPS. Methods This retrospective propensity score matching (PSM) study included advanced HCC patients treated with prior TIPS followed by TKIs, PD-1 inhibitors, and TACE between January 2021 and January 2023. Patients were matched with a control group of HCC patients who had not undergone TIPS (non-TIPS). Outcome measures included objective response rate (ORR) using modified RECIST (mRECIST v1.1), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety assessed by CTCAE v5.0. Results A total of 172 patients were included before PSM. After PSM, 42 patients with prior TIPS were matched with 71 non-TIPS patients. ORR was 31.0% in the TIPS group and 57.7% in the non-TIPS group (p = 0.007), Both PFS and OS were longer in the non-TIPS group, with a median PFS of 7.9 months for TIPS patients versus 12.3 months for non-TIPS patients (hazard ratio [HR] = 2.253, p < 0.001), and a median OS of 13.5 months versus 21.1 months, respectively (HR = 2.282, p = 0.002). Treatment-related adverse events showed no significant differences between the two groups. Conclusion TACE combined with TKIs and PD-1 inhibitors showed lower efficacy in HCC patients with prior TIPS, but it remains a viable option, providing a favorable safety profile and effective disease control.
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Affiliation(s)
- Kai Xiong
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Kuiyuan Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Yulong Liu
- Department of Vascular Intervention, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
| | - Huajin Pang
- Division of Vascular and Interventional Radiology, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Peng Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yalu Zheng
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Tengzheng Li
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Zhangyun Li
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Moran Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Dandan Zheng
- Department of Radiation Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaohong Huang
- Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Mingrong Cao
- Department of Hepatobiliary and pancreatic Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
| | - Qiang Li
- Department of Hepatobiliary and pancreatic Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
| | - Junjie Liang
- Department of Hepatobiliary and pancreatic Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
| | - Huizhen Fan
- Department of Gastroenterology, The People′s Hospital of Yichun City, Yichun, Jiangxi, China
| | - Deju Li
- Department of Vascular Surgery, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Jian Sun
- Department of Hepatobiliary and pancreatic Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
| | - Zhili Wen
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
| | - Yuchuan Jiang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang University, Nanchang, Jiangxi, China
- Department of Hepatobiliary and pancreatic Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China
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Yuan L, Wang Y, Cheng J, Lin S, Ma A, Li K, Zheng Y, Zeng Z, Ke A, Gao C, Du S. Cancer-derived exosomal circTMEM56 enhances the efficacy of HCC radiotherapy through the miR-136-5p/STING axis. Cancer Biol Med 2025; 22:j.issn.2095-3941.2024.0544. [PMID: 40269559 PMCID: PMC12032838 DOI: 10.20892/j.issn.2095-3941.2024.0544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 02/26/2025] [Indexed: 04/25/2025] Open
Abstract
OBJECTIVE Although the role of circular RNAs (circRNAs) in tumor progression and immune regulation is well-known, the specific circRNA molecules that mediate immune responses after radiotherapy (RT) and the underlying mechanisms have not been identified. METHODS Cytometry with time-of-flight (CyTOF) was used to analyze blood samples from patients with liver cancer exhibiting abscopal effects (AEs) after stereotactic body radiotherapy (SBRT) to quantify the number of dendritic cells (DCs) and CD8+ T cells and interferon-beta (IFN-β) level. circTMEM56 and IFN-β levels were measured in 76 patients with liver cancer using qPCR and ELISA. Immunohistochemistry validated circTMEM56 and CD141 staining in tissues. The interaction between circTMEM56, miR-136-5p, and STING, as well as the impact on anti-tumor immunity, was verified using circTMEM56-specific probes, dual-luciferase activity assays, proteomics analysis, and western blot analysis. RESULTS The role of circTMEM56 in enhancing anti-tumor immunity and response to RT in hepatocellular carcinoma (HCC) was determined. Higher circTMEM56 levels were linked to an improved RT response and better clinical outcomes in patients with HCC. circTMEM56 enhanced cGAS-STING signaling, increased the number of tumor-infiltrating CD8+ T cells, and elevated the serum IFN-β levels. Moreover, circTMEM56 administration significantly boosted the response to RT in tumors with low circTMEM56 expression. CONCLUSIONS High circTMEM56 expression in HCC modulates the distant effects of HCC RT by activating the cGAS-STING pathway to reshape the tumor microenvironment. This study provides a new approach to improve RT efficacy for HCC.
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Affiliation(s)
- Li Yuan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Yue Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Junjie Cheng
- Graduate School of Bengbu Medical University, Bengbu 233030, China
| | - Shilin Lin
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Aying Ma
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Kunchao Li
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330000, China
| | - Yiming Zheng
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Zhaochong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Aiwu Ke
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Chao Gao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, China
| | - Shisuo Du
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Davis E, Ermi AG, Sarkar D. Astrocyte Elevated Gene-1/Metadherin (AEG-1/MTDH): A Promising Molecular Marker and Therapeutic Target for Hepatocellular Carcinoma. Cancers (Basel) 2025; 17:1375. [PMID: 40282551 PMCID: PMC12025727 DOI: 10.3390/cancers17081375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/16/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. The 5-year survival rate has been estimated to be less than 20% while its incidence rates have more than tripled since the 1980s. Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) has been demonstrated to have an influential role in HCC progression and the development of an aggressive phenotype. AEG-1 has been shown to be upregulated in many cancers, including HCC. Studies have shown that it plays a crucial role in the proliferation, invasion and metastasis, and evasion of apoptosis in HCC. Its relationship with proteins and pathways, such as MYC, SND1, PI3K/AKT, and other signaling pathways demonstrates its pertinent role in oncogenic development and relevance as a biomarker and therapeutic target. Recent studies have shown that AEG-1 is present in tumor tissues, and the anti-AEG-1 antibody is detected in the blood of cancer patients, demonstrating its viability as a diagnostic/prognostic marker. This review paper shines light on recent findings regarding the molecular implications of AEG-1, with emphasis on its role of regulating metabolic dysfunction-associated steatohepatitis (MASH), a key predisposing factor for HCC, new treatment strategies targeting AEG-1, and challenges associated with analyzing this intriguing molecule.
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Affiliation(s)
- Eva Davis
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Ali Gawi Ermi
- Department of Cellular, Molecular and Genetic Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Department of Cellular, Molecular and Genetic Medicine, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
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Yao RR, Zhang QB, Ge MX, Li L, Li J, Zhou XL, Wang ZX, Liang XH. The safety and efficacy of atezolizumab for recurrent primary liver cancer after liver transplantation. Discov Oncol 2025; 16:553. [PMID: 40244542 PMCID: PMC12006625 DOI: 10.1007/s12672-025-02299-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 04/02/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have been proved to have certain therapeutic effects for primary liver cancer. However, the efficacy and safety of their applications in liver transplantation (LT) recipients with recurrent tumor remained unclear and even controversial. METHODS A retrospective study was conducted to evaluate the safety and efficacy of atezolizumab in LT recipients with recurrent PLC from August 1, 2019, to July 1, 2022. The primary endpoint was the incidence of allograft rejection, while secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Additionally, risk factors associated with ICI-related rejection were analyzed. RESULTS A total of eight LT recipients with recurrent PLC were included in the study, comprising six cases of hepatocellular carcinoma (HCC) and two cases of intrahepatic cholangiocarcinoma (ICC). The median number of atezolizumab treatment cycles was 3 (range, 1-10). Graft rejection occurred in 25% of patients (2/8). The median overall survival (mOS) from the initiation of atezolizumab was 6.2 months (range, 0.7-12.5 months), with a mortality rate of 75% (6/8). The ORR (complete response [CR] + partial response [PR]) was 28.5% (2/7), and the disease control rate (DCR; CR + PR + stable disease [SD]) was 42.9% (3/7). Time from LT to recurrence (P = 0.008) and Interval time from LT to atezolizumab (P = 0.005) were associated with liver rejection. CONCLUSIONS Atezolizumab demonstrated a certain degree of efficacy as a salvage treatment for patients with recurrent HCC and ICC after LT. However, given the potential risk of allograft rejection, careful evaluation of safety is essential before initiating ICI therapy. Moreover, close monitoring and timely intervention are necessary during treatment to mitigate the risk of rejection. Future studies should further explore the optimal timing and strategies for ICI administration in this patient population.
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Grants
- (2020QD010) Scientific Research Foundation of Huashan Hospital, Fudan University
- (2020QD010) Scientific Research Foundation of Huashan Hospital, Fudan University
- (2020QD010) Scientific Research Foundation of Huashan Hospital, Fudan University
- (2020QD010) Scientific Research Foundation of Huashan Hospital, Fudan University
- (2020QD010) Scientific Research Foundation of Huashan Hospital, Fudan University
- 82071797, 82173093, 82241225 Natural Science Foundation of China
- 82071797, 82173093, 82241225 Natural Science Foundation of China
- 82071797, 82173093, 82241225 Natural Science Foundation of China
- (SHDC2020CR2021B) the Shanghai Hospital Development Center
- (SHDC2020CR2021B) the Shanghai Hospital Development Center
- (SHDC2020CR2021B) the Shanghai Hospital Development Center
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Affiliation(s)
- Rong-Rong Yao
- Department of Oncology, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Quan-Bao Zhang
- Liver Transplantation Center, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
- Institute of Organ Transplantation, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Meng-Xi Ge
- Department of Oncology, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Li Li
- Liver Transplantation Center, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
- Institute of Organ Transplantation, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Jing Li
- Department of Oncology, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Xin-Li Zhou
- Department of Oncology, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China
| | - Zheng-Xin Wang
- Liver Transplantation Center, Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China.
- Institute of Organ Transplantation, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China.
| | - Xiao-Hua Liang
- Department of Oncology, Huashan Hospital, Fudan University, 12 Urumqi Road(M), Shanghai, 200040, China.
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Zhang T, Ren C, Yang Z, Zhang N, Tang H. Exploration of the role of immune cells and cell therapy in hepatocellular carcinoma. Front Immunol 2025; 16:1569150. [PMID: 40308592 PMCID: PMC12040661 DOI: 10.3389/fimmu.2025.1569150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 03/27/2025] [Indexed: 05/02/2025] Open
Abstract
Hepatocellular carcinoma stands as one of the foremost contributors to cancer-associated fatalities globally, and the limitations of traditional treatment methods have prompted researchers to explore new therapeutic options. Recently, cell therapy has emerged as a promising approach for HCC, showing significant potential in improving patient outcomes. This review article explores the use of cell therapy for HCC, covering different types, the mechanisms behind their effectiveness, recent advancements in clinical trials, and ongoing challenges. This article aims to provide insightful perspectives for future research and clinical applications in treating HCC by synthesizing current knowledge.
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Affiliation(s)
- Tao Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Cong Ren
- The Second Clinical College, Chongqing Medical University, Chongqing, China
| | - Zhanyu Yang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Ning Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Haowen Tang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
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Liang LW, Luo RH, Huang ZL, Tang LN. Clinical observation of nivolumab combined with cabozantinib in the treatment of advanced hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:103631. [PMID: 40235875 PMCID: PMC11995320 DOI: 10.4251/wjgo.v17.i4.103631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/25/2024] [Accepted: 02/07/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a particularly serious kind of liver cancer. Liver cancer ranks third in terms of mortality rate worldwide, putting it among the leading causes of deaths from cancer. HCC is the primary kind of liver cancer and makes up the vast majority of cases, accounting for approximately 90% of occurrences. Numerous research have verified this information. the progress of fatty liver, alcohol induced cirrhosis, smoking habits, obesity caused by overweight, and metabolic diseases such as diabetes. The treatment strategies for HCC can be divided into two categories: One is curative treatment, including liver transplantation, surgical resection, and ablation therapy or selective arterial radiation embolization, aimed at completely eliminating the lesion; Another type is non curative treatment options, including transarterial chemoembolization and systemic therapy, which focus on controlling disease progression and prolonging patient survival. The majority of HCC patients are found to be in an advanced stage and need systemic therapy. Sorafenib and lenvatinib are frequently used as first-line medications in traditional HCC treatment to slow the disease's progression. For second-line treatment, regorafenib, cabozantinib, or remdesizumab are used to inhibit tumors through different mechanisms and prolong survival. In recent years, with the in-depth exploration of the pathogenesis and progression mechanism of HCC, as well as the rapid progress within the domain of tumor immunotherapy, the treatment prospects for advanced HCC patients have shown a positive transformation. This transformation is reflected in the fact that more and more patients are gradually gaining significant and considerable therapeutic advantages from advanced immunotherapy regimens, bringing unprecedented improvements to their treatment outcomes. In order to enable activated T cells to attack tumor cells, immune checkpoint inhibitors interfere with the inhibitory. AIM To evaluate the effects of nivolumab in combination with cabozantinib on patient tumor markers and immune function, as well as the therapeutic efficacy of this combination in treating advanced HCC, a study was conducted. METHODS In all, 100 patients with advanced HCC who were brought to our hospital between July 2022 and July 2023 and who did not match the requirements for surgical resection had their clinical data thoroughly analyzed retrospectively in this study. Among them, half of the patients (50 cases) only received oral cabozantinib as a single treatment regimen (set as the control group), while the other half of the patients (50 cases) received intravenous infusion of nivolumab in addition to oral cabozantinib (set as the observation group). The objective of the probe is to examine the variations in disease control rate (DCR) and objective response rate (ORR) between two groups; At the same time, changes in the levels of T lymphocyte subsets (CD3+, CD4+, CD8+) and tumor markers, including AFP, GP-73, and AFP-L3, were evaluated; In addition, changes in liver and kidney function indicators and adverse reactions during treatment were also monitored. For patients with advanced HCC, this research also calculated and analyzed the progression free survival of two patient groups throughout the course of a 12-month follow-up to assess the effectiveness and safety of this therapeutic approach. RESULTS Upon comparing baseline information for both groups of subjects before treatment, it was found that no statistically significant alterations had occurred (P > 0.05). After the therapeutic intervention, the observation group and control group's ORR and DCR differed statistically significantly (P < 0.05). The observation group's scores significantly improved. Subsequent examination revealed that the observation group's T lymphocyte subset levels had significantly changed, mostly exhibiting an increase in CD3+, CD4+, and CD4+/CD8+ levels while CD8+ levels had comparatively dropped. There was a significant difference (P < 0.05) between these changes and those in the control group. The observation group also showed positive improvements in tumor markers; AFP, GP-73, and AFP-L3 levels were considerably lower in the group under observation than in the control group, with statistically significant differences (P < 0.05). When liver function was assessed, total bilirubin and alanine aminotransferase were found to be considerably lower in the observation group than in the control group (P < 0.05). The incidence of adverse responses was not statistically significant (P > 0.05), indicating that the incidence of adverse responses did not differ significantly between the two groups. CONCLUSION When treating advanced HCC, nivolumab and cabozantinib together have the ability to increase T lymphocyte numbers, reduce tumor marker levels, effectively prolong survival time, and have better efficacy than simple control treatment, with good safety.
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Affiliation(s)
- Lu-Wen Liang
- Infection and Liver Disease Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400000, China
| | - Rong-Hong Luo
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Zhi-Li Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
| | - Li-Na Tang
- Department of Infectious Diseases, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
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Fu L, Li S, Mei J, Li Z, Yang X, Zheng C, Li N, Lin Y, Cao C, Liu L, Huang L, Shen X, Huang Y, Yun J. BIRC2 blockade facilitates immunotherapy of hepatocellular carcinoma. Mol Cancer 2025; 24:113. [PMID: 40223121 PMCID: PMC11995630 DOI: 10.1186/s12943-025-02319-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 04/01/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND The effectiveness of immunotherapy in hepatocellular carcinoma (HCC) is limited, however, the molecular mechanism remains unclear. In this study, we identified baculoviral IAP repeat-containing protein 2 (BIRC2) as a key regulator involved in immune evasion of HCC. METHODS Genome-wide CRISPR/Cas9 screening was conducted to identify tumor-intrinsic genes pivotal for immune escape. In vitro and in vivo models demonstrated the role of BIRC2 in protecting HCC cells from immune killing. Then the function and relevant signaling pathways of BIRC2 were explored. The therapeutic efficacy of BIRC2 inhibitor was examined in different in situ and xenograft HCC models. RESULTS Elevated expression of BIRC2 correlated with adverse prognosis and resistance to immunotherapy in HCC patients. Mechanistically, BIRC2 interacted with and promoted the ubiquitination-dependent degradation of NFκB-inducing kinase (NIK), leading to the inactivation of the non-canonical NFκB signaling pathway. This resulted in the decrease of major histocompatibility complex class I (MHC-I) expression, thereby protecting HCC cells from T cell-mediated cytotoxicity. Silencing BIRC2 using shRNA or inhibiting it with small molecules increased the sensitivity of HCC cells to immune killing. Meanwhile, BIRC2 blockade improved the function of T cells both in vitro and in vivo. Targeting BIRC2 significantly inhibited tumor growth, and enhanced the efficacy of anti-programmed death protein 1 (PD-1) therapy. CONCLUSIONS Our findings suggested that BIRC2 blockade facilitated immunotherapy of HCC by simultaneously sensitizing tumor cells to immune attack and boosting the anti-tumor immune response of T cells.
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Affiliation(s)
- Lingyi Fu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Shuo Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Jie Mei
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ziteng Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Xia Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Chengyou Zheng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Nai Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Yansong Lin
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Chao Cao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Lixuan Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Liyun Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Xiujiao Shen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Yuhua Huang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China
| | - Jingping Yun
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
- Department of Pathology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.
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Sun B, Liu J, Liu X, Li J, Zhang G, Sun T, Zheng C, Kan X. Oncolytic peptide LTX-315 plus an anti-CTLA-4 antibody induces a synergistic anti-cancer immune response in residual tumors after radiofrequency ablation of hepatocellular carcinoma. Cell Death Dis 2025; 16:288. [PMID: 40222972 PMCID: PMC11994779 DOI: 10.1038/s41419-025-07622-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 03/29/2025] [Accepted: 04/02/2025] [Indexed: 04/15/2025]
Abstract
Preventing tumor recurrence after radiofrequency ablation (RFA) of malignant solid tumors with large size or in high-risk locations represents a great challenge. In this study, we explored the feasibility of using oncolytic peptide LTX-315 plus an anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody for inhibiting residual tumors after RFA of hepatocellular carcinoma (HCC). In in vitro experiment, the CD8+T cells from Hepa1-6 tumors, after being subjected to three different treatments (control, iRFA, iRFA + LTX-315), were extracted and were then co-cultured with Hepa1-6 cells and an anti-CTLA-4 antibody. The enzyme-linked immunospot, flow cytometry, and cell counting kit-8 assay were employed to assess the cytotoxicity of extracted CD8+T cells on Hepa1-6 cells. In in vivo experiment, different murine orthotopic HCC models were variously treated by: (1) pseudo iRFA + phosphate-buffered saline (PBS); (2) iRFA + PBS; (3) iRFA + LTX-315; (4) iRFA + anti-CTLA-4 antibody; and (5) iRFA + LTX-315 + anti-CTLA-4 antibody. The treatment effects were compared among different groups and were pathologically confirmed. The possible mechanisms of the combination treatment (LTX-315+anti-CTLA-4 antibody) for residual tumors after iRFA of HCC were explored. LTX-315 significantly reduced the PD-1 expression and significantly increased CTLA-4 expression of CD8+T cells in residual tumors, and additional treatment of anti-CTLA-4 antibody could significantly enhance the cytotoxicity of CD8+T cells for Hepa1-6 cells in vitro experiments. Compared with the other treatments, the combined treatment of LTX-315 with anti-CTLA-4 antibody achieved a better tumor response and longer survival, and it could synergistically activate the cGAS-STING pathway and elicit an immunogenic cell death, leading to a strong anti-tumor immunity after iRFA of HCC. The immunosuppressive microenvironment of residual tumors was significantly improved by the combination therapy with a significantly increased ratio of M1-like tumor-associated macrophages to M2-like tumor-associated macrophages, a significantly decreased infiltration of regulatory T cells and myeloid-derived suppressor cells, and a significantly lower expression of PD-1 and CTLA-4. Overall, the results of this study demonstrated that LTX-315 plus anti-CTLA-4 antibody could synergistically improve the immunosuppressive microenvironment of residual tumors and induce a strong anti-tumor immunity after iRFA of HCC. This combination treatment strategy may offer a new alternative to reduce the tumor recurrence after RFA of malignant solid tumors with large sizes or in high-risk locations.
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Affiliation(s)
- Bo Sun
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Jiayun Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Xiaocui Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Jing Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Guilin Zhang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Tao Sun
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China.
| | - Xuefeng Kan
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Provincial Clinical Research Center for Precision Radiology & Interventional Medicine, Wuhan, China.
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China.
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Wu M, Zou F, He S, Pi Y, Song Y, Chen S, Li L. Serum Osteopontin Enhances Hepatocellular Carcinoma Diagnosis and Predicts Anti-PD-L1 Immunotherapy Benefit. J Hepatocell Carcinoma 2025; 12:729-745. [PMID: 40255899 PMCID: PMC12007010 DOI: 10.2147/jhc.s514144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 04/05/2025] [Indexed: 04/22/2025] Open
Abstract
Background Osteopontin (OPN), a phosphorylated glycoprotein encoded by SPP1, critical in hepatic inflammation and fibrosis, requires further investigation for its role on hepatocellular carcinoma (HCC) and predictive value for anti-programmed cell death ligand 1 (anti-PD-L1) immunotherapy responses. Methods Publicly available datasets were utilized to explore OPN expression in HCC. A retrospective cohort study involving 316 participants, recruited from January 2015 to March 2017. Serum OPN levels were measured by enzyme-linked immunosorbent assay. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves, a logistic regression model was developed for early HCC diagnosis. Prospective follow-up was conducted from 2017 to 2024 to evaluate overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier analyses. The survival benefit of anti-PD-L1 immunotherapy for patients with OPN patterns was investigated. Results Serum OPN levels were significantly elevated in HCC compared to chronic liver disease and healthy individuals (both p <0.001). The area under the curve (AUC) for OPN was 0.903, with 88.2% sensitivity and 83.3% specificity, significantly superior to AFP alone (AUC: 0.707). A combined diagnostic model integrating OPN with alpha-fetoprotein (AFP) and aspartate aminotransferase (AST) enhanced accuracy further (AUC: 0.941). High OPN levels indicated higher tumor burden and predicted worse clinical outcomes (mean OS: 49.1 vs 75.1 months; mean DFS: 37.7 vs 60.9 months, respectively; both log-rank p <0.001). Anti-PD-L1 immunotherapy significantly prolonged survival (OS: 62.9 vs 38.0 months, p = 0.009; DFS: 48.7 vs 28.6 months, p = 0.033) in patients with OPN high pattern. Conclusion Serum OPN demonstrates standalone diagnostic value for HCC and enhances conventional biomarker panels when combined with AFP and AST. OPN high pattern identify patients likely to benefit from anti-PD-L1 immunotherapy, suggesting its dual utility as a diagnostic and predictive biomarker.
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Affiliation(s)
- Miantao Wu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Laboratory Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Fei Zou
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning, Chongqing, People’s Republic of China
| | - Suyin He
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Yingqi Pi
- Department of Clinical Laboratory, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China
| | - Yiling Song
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Laboratory Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Shulin Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Laboratory Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
| | - Linfang Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
- Department of Laboratory Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China
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Guo X, Zhao Z, Zhu L, Liu S, Zhou L, Wu F, Fang S, Chen M, Zheng L, Ji J. The evolving landscape of biomarkers for systemic therapy in advanced hepatocellular carcinoma. Biomark Res 2025; 13:60. [PMID: 40221793 PMCID: PMC11993949 DOI: 10.1186/s40364-025-00774-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Accepted: 03/29/2025] [Indexed: 04/14/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. With the approval of multiple first- and second-line agents, especially the combination therapies based on immune checkpoint inhibitor (ICI) regimens, the landscape of systemic therapy for advanced HCC (aHCC) is more diverse than ever before. The efficacy of current systemic therapies shows great heterogeneity in patients with aHCC, thereby identifying biomarkers for response prediction and patient stratification has become an urgent need. The main biomarkers for systemic therapy in hepatocellular carcinoma are derived from peripheral blood, tissues, and imaging. Currently, the understanding of the clinical response to systemic therapy indicates unequivocally that a single biomarker cannot be used to identify patients who are likely to benefit from these treatments. In this review, we provide an integrated landscape of the recent development in molecular targeted therapies and ICIs-based therapies, especially focusing on the role of clinically applicable predictive biomarkers. Additionally, we further highlight the latest advancements in biomarker-driven therapies, including targeted treatments, adoptive cell therapies, and bispecific antibodies.
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Affiliation(s)
- Xinyu Guo
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Zhongwei Zhao
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Lingyi Zhu
- The 2nd Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, China
| | - Shuang Liu
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Lingling Zhou
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Fazong Wu
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Shiji Fang
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Minjiang Chen
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China
| | - Liyun Zheng
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China.
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China.
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
| | - Jiansong Ji
- Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, School of Medicine, Lishui Hospital, Zhejiaing University, Lishui, 323000, China.
- Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Central Hospital, Lishui, 323000, China.
- Zhejiang Key Laboratory of Imaging and Interventional Medicine, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, 323000, China.
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Liu Z, Mao Y, Wang S, Zheng H, Yang K, Yang L, Huang P. A bibliometric and visual analysis of the impact of senescence on tumor immunotherapy. Front Immunol 2025; 16:1566227. [PMID: 40292294 PMCID: PMC12021824 DOI: 10.3389/fimmu.2025.1566227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
Background Recently, many studies have focused on the relationship between senescence and immunotherapy in cancer treatment. However, relatively few studies have examined the intrinsic links between the three. Whether these studies can act synergistically in the fight against cancer and the specific links between them are still unclear. Methods We extracted, quantified, and visualized data from the literature (n = 2396) for the period 2004-2023 after rigorous quality control using citespace, GraphPad Prism, the R software package, and VOSviewer. Results Linear fit analyses were generated to predict the number of annual publications and citations as a function of the top-performing authors, journals, countries, and affiliations academically over the past two decades such as Weiwei, Aging-us, China, and the UT MD Anderson Cancer Center. Vosviewer-based hierarchical clustering further categorized study characteristics into six clusters, including two major clusters of immunotherapy research, immunosenescence-related research factors, and timeline distributions suggesting that cellular senescence and tumor progression is a relatively new research cluster that warrants further exploration and development. Study characterization bursts and linear regression analyses further confirmed these findings and revealed other important results, such as aging (a = 1.964, R² = 0.6803) and immunotherapy (a = 16.38, R² = 0.8812). Furthermore, gene frequency analysis in this study revealed the most abundant gene, APOE, and SIRT1-7 proteins. Conclusion The combination of aging therapies with tumor immunotherapies is currently in its preliminary stages. Although senescence has the greatest impact on ICB therapies, mechanistic investigations, and drug development for APOE and sirt1-7 (Sirtuins family) targets may be the key to combining senescence therapies with immunotherapies in the treatment of tumors.
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Affiliation(s)
- Zixu Liu
- Center for Evidence-Based Medicine, School of Public Health, Jiangxi Medical College. Nanchang University, Nanchang, China
- Jiangxi Province Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, Nanchang, China
- First Clinical Medicine School, Nanchang University, Nanchang, China
| | - Yuchen Mao
- First Clinical Medicine School, Nanchang University, Nanchang, China
| | - Shukai Wang
- First Clinical Medicine School, Nanchang University, Nanchang, China
| | - Haoyu Zheng
- School of Stomatology, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Kangping Yang
- Department of Gastroenterological Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Liang Yang
- Department of Gastroenterological Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Peng Huang
- Center for Evidence-Based Medicine, School of Public Health, Jiangxi Medical College. Nanchang University, Nanchang, China
- Jiangxi Province Key Laboratory of Preventive Medicine, Jiangxi Medical College, Nanchang University, Nanchang, China
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Yoo A, Chen J, Sarma V, Arundel C. Remote presentation of nivolumab-induced bullous pemphigoid in hepatocellular carcinoma. BMJ Case Rep 2025; 18:e263285. [PMID: 40199591 DOI: 10.1136/bcr-2024-263285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025] Open
Abstract
A man in his 70s with a history of unresectable hepatocellular carcinoma (HCC) treated with nivolumab presented with a blistering rash 14 months after nivolumab initiation. Biopsies and direct immunofluorescence confirmed the diagnosis of bullous pemphigoid (BP). BP is an autoimmune skin disorder in which autoantibodies bind to the dermal-epidermal junction. It is a rare sequela of programmed cell death protein-1 (PD-1) inhibitors that can develop after treatment initiation and typically resolve soon after discontinuation. Most cases are reported in melanoma and non-small cell lung cancers, and rarely in HCC irrespective of the timing of onset. We describe a rare presentation of remote BP with PD-1 inhibitor use in HCC. PD-1 inhibitor-induced BP is a rare cutaneous immune-related adverse event, and this case highlights the variability in onset and chronicity.
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Affiliation(s)
- Ashley Yoo
- Internal Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Joyce Chen
- Internal Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Vivek Sarma
- The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Cherinne Arundel
- Internal Medicine, DC VA Medical Center, Washington, District of Columbia, USA
- Internal Medicine, George Washington University Hospital, Washington, District of Columbia, USA
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De la Torre-Aláez M, Matilla A, Varela M, Iñarrairaegui M, Reig M, Lledó JL, Arenas JI, Lorente S, Testillano M, Márquez L, Iserte G, Argemí J, Gómez-Martin C, Rodríguez-Fraile M, Bilbao JI, Pollock RF, Pöhlmann J, Agirrezabal I, Sangro B. Health-related quality of life in patients with unresectable hepatocellular carcinoma treated with SIRT and nivolumab: a sub-analysis of the NASIR-HCC trial. J Patient Rep Outcomes 2025; 9:39. [PMID: 40198533 PMCID: PMC11978598 DOI: 10.1186/s41687-025-00873-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 03/28/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND The health-related quality of life (HRQoL) impact of therapies for hepatocellular carcinoma (HCC) influences decision-making and treatment outcomes. The present study reports HRQoL results from NASIR-HCC, a single-arm study of selective internal radiation therapy (SIRT) with Y90 resin microspheres followed by nivolumab for unresectable HCC. METHODOLOGY Participants completed the EQ-5D-3 L, EQ-VAS, and FACT-Hep at baseline and on the first day of each nivolumab cycle. Linear mixed-effect models were used to calculate changes in outcomes in participants with the baseline and ≥ 1 follow-up measurement. Changes were assessed for clinical meaningfulness versus published minimally important differences. RESULTS Thirty-two patients from NASIR-HCC were included. Completion rates exceeded 70% at 62% of time points. Across EQ-5D-3 L domains, minimal changes were reported. Most patients had no problems at almost all time points. Mean index values were 0.864 at baseline and 0.763 in cycle 8, but this difference was not clinically meaningful. The small EQ-VAS increase, from 74.8 at baseline to 75.9 in cycle 8, was also not clinically meaningful. The various FACT scales remained stable, although transient but not clinically meaningful declines occurred for some scales. The median time to deterioration was 5.5 months for the FACT-Hep score. CONCLUSIONS Combining SIRT with nivolumab did not compromise HRQoL in patients with unresectable HCC. Study results were limited by the small number of patients but, combined with the previously reported clinical outcomes, suggested that the treatment combination deserves further consideration in this difficult-to-treat population. TRIAL REGISTRATION NUMBER/DATE OF REGISTRATION NCT03380130. First submitted on 2017-10-20; https://clinicaltrials.gov/study/NCT03380130 .
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Affiliation(s)
- Manuel De la Torre-Aláez
- Liver Unit and HPB Oncology Area, Clínica Universidad de Navarra, Madrid, Spain
- Centro de Investigación Biomédica en Red de Efermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Ana Matilla
- Centro de Investigación Biomédica en Red de Efermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Digestive Diseases Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - María Varela
- Liver Unit, Hospital Universitario Central de Asturias, IUOPA, ISPA, Universidad de Oviedo, Oviedo, FINBA, Spain
| | - Mercedes Iñarrairaegui
- Centro de Investigación Biomédica en Red de Efermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra, Pamplona, Spain
| | - María Reig
- Centro de Investigación Biomédica en Red de Efermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Liver Oncology Unit, Liver Unit, ICMDM, Hospital Clinic, Barcelona, Spain
- BCLC Group, IDIBAPS, Universidad de Barcelona, Barcelona, Spain
| | - José Luis Lledó
- Centro de Investigación Biomédica en Red de Efermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Gastroenterology and Hepatology Service, Hospital Universitario Ramon y Cajal, IRYCIS, Universidad de Alcalá, Madrid, Spain
| | | | - Sara Lorente
- Liver Unit, Hospital Clínico Lozano Blesa, Zaragoza, Spain
| | | | - Laura Márquez
- Digestive Diseases Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Gemma Iserte
- Centro de Investigación Biomédica en Red de Efermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Liver Oncology Unit, Liver Unit, ICMDM, Hospital Clinic, Barcelona, Spain
- BCLC Group, IDIBAPS, Universidad de Barcelona, Barcelona, Spain
| | - Josepmaria Argemí
- Centro de Investigación Biomédica en Red de Efermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra, Pamplona, Spain
| | | | | | - José I Bilbao
- Interventional Radiology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Richard F Pollock
- Covalence Research Ltd, Rivers Lodge, West Common, Harpenden, AL5 2JD, UK
| | - Johannes Pöhlmann
- Covalence Research Ltd, Rivers Lodge, West Common, Harpenden, AL5 2JD, UK.
| | | | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clínica Universidad de Navarra, Madrid, Spain
- Centro de Investigación Biomédica en Red de Efermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra, Pamplona, Spain
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Tian H, Wan C. Comparative efficacy and safety of transarterial chemoembolization combined with tyrosine kinase inhibitors and immune checkpoint inhibitors versus tyrosine kinase inhibitors and immune checkpoint inhibitors alone in advanced hepatocellular carcinoma: a systematic review and meta-analysis. World J Surg Oncol 2025; 23:126. [PMID: 40197348 PMCID: PMC11974228 DOI: 10.1186/s12957-025-03788-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 03/29/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and advanced-stage disease presents significant therapeutic challenges. Combining transarterial chemoembolization (TACE) with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has emerged as a promising strategy to enhance treatment efficacy. This meta-analysis evaluates efficacy and safety of TACE + TKIs + ICIs compared to TKIs + ICIs alone in patients with HCC. METHODS A systematic search was conducted across "PubMed", "Web of Science", "Cochrane Library", "Scopus", "Google Scholar", and "Embase" to screen studies up to November 2024. Studies comparing TACE + TKIs + ICIs with TKIs + ICIs alone in advanced HCC were included. Outcomes of interest included objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and adverse events. Results were reported as relative risk (RR) or hazard ratios (HR) with 95% confidence intervals (CI). Funnel plots was used to assess publication bias. RESULTS Ten studies comprising 1999 patients were included. The combination of TACE + TKIs + ICIs marked improved ORR (RR = 1.81, 95%CI:1.57-2.09, P < 0.00001) and DCR (RR = 1.32, 95%CI: 1.19-1.46, P < 0.00001) comparing with TKIs + ICIs alone. OS and PFS were also significantly prolonged in combination group, with HR of 0.55 (95%CI:0.48-0.63, P < 0.00001) and 0.73 (95%CI:0.65-0.82, P < 0.00001), respectively. Adverse events such as pain (RR = 3.94, 95%CI:2.40-6.47, P < 0.001) and nausea/vomiting (RR = 2.28, 95% CI:1.56-3.33, P < 0.001) were more frequent in the TACE + TKIs + ICIs group, though rates of hypertension, diarrhea, and rash were similar between groups. Funnel plots indicated minimal publication bias for primary outcomes. CONCLUSIONS The combination of TACE, TKIs, and ICIs significantly improves ORR, DCR, OS, and PFS compared to TKIs and ICIs alone, demonstrating superior efficacy with an acceptable safety profile. These findings provide evidence for the integration of TACE with systemic therapies in the management of HCC.
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Affiliation(s)
- Hengyu Tian
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, No, China
| | - Chidan Wan
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, No, China.
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Liu GM, Guo R, Xu JW. A bibliometric and visual analysis based on immune checkpoint inhibitors for hepatocellular carcinoma: 2014 - 2024. Front Pharmacol 2025; 16:1520055. [PMID: 40260385 PMCID: PMC12009821 DOI: 10.3389/fphar.2025.1520055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 03/24/2025] [Indexed: 04/23/2025] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of hepatocellular carcinoma (HCC), especially those with unresectable advanced stages. The field has progressed rapidly, and the research hotspots have significantly changed compared to previous years. The study aims to comprehensively review and analyze the development history, knowledge structure, current research focus, and emerging trends in ICIs for HCC. Materials and methods Reviews and articles published in English from The Web of Science Core Collection (WoSCC) database from 2014 to 2024 were systemically retrieved. Citespace, VOSviewer, and Bibliometrix R package were used for further bibliometric analysis and visualization for countries, institutions, authors, references, and keywords. Results 2,941 records were included for analysis. The literature on ICIs for HCC has continued to grow steadily over the past decade. Three major research centers have emerged: North America, Europe, and East Asia. The Chinese institution has the highest publication volume, but Kudo Masatoshi from Japan has the highest number of publications. At the same time, Richard S. Finn from the United States leads in citations and co-citations. The most prolific journal is "Cancers". The clustering and Timeline view of critical literature and keywords indicated that research on ICIs for HCC is rapidly advancing toward a more evidence-based, personalized, and multimodal approach. Immune evasion mechanisms, predictive biomarkers, and high-quality clinical trials focusing on Novel combination, conversion, and perioperative therapies, including ICIs, are emerging hotspots. Conclusion This study highlights the groundbreaking advancements of ICIs in treating HCC and shows a trend rapidly advancing towards a more evidence-based, personalized, and multimodal approach. The study updated the current understanding of ICIs in hepatocellular carcinoma and identified vital future directions for research, such as the exploration of mechanisms of immune evasion, developing predictive biomarkers, and combining therapy strategies.
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Affiliation(s)
- Gao-Min Liu
- Meizhou Clinical Medical College of Shantou University Medical College, Meizhou, China
- Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Meizhou, China
| | - Rui Guo
- Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Meizhou, China
| | - Ji-Wei Xu
- Meizhou Clinical Medical College of Shantou University Medical College, Meizhou, China
- Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Meizhou, China
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