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Llopiz D, Silva L, Ruiz M, Castro-Alejos C, Aparicio B, Vegas L, Infante S, Santamaria E, Sarobe P. MERTK inhibition improves therapeutic efficacy of immune checkpoint inhibitors in hepatocellular carcinoma. Oncoimmunology 2025; 14:2473165. [PMID: 40029206 PMCID: PMC11881874 DOI: 10.1080/2162402x.2025.2473165] [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] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/29/2025] [Accepted: 02/24/2025] [Indexed: 03/05/2025] Open
Abstract
Immunotherapy with immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) patients only achieves response rates of 25%-30%, indicating the necessity of new therapies for non-responder patients. Since myeloid-related suppressive factors are associated with poor responses to ICI in a subgroup of HCC patients, modulation of these targets may improve response rates. Our aim was to characterize the expression of the efferocytosis receptor MERTK in HCC and to analyze its potential as a new therapeutic target. In HCC patients, MERTK was expressed by myeloid cells and was associated with poorer survival. In a murine HCC model with progressive myeloid cell infiltration, MERTK was detected in dendritic cells and macrophages with an activated phenotype, which overexpressed the checkpoint ligand PD-L1. Concomitant expression of PD-1 in tumor T-cells suggested the pertinence of combined PD-1/PD-L1 and MERTK blockade. In vivo experiments in mice showed that inhibition of MERTK improved the therapeutic effect promoted by anti-PD-1 or by ICI combinations currently approved for HCC. This effect was associated with enhanced tumor infiltration and superior activity of antigen presenting cells and effector lymphocytes. Our results indicate that MERTK may behave as a relevant target for immunotherapeutic combinations in those HCC patients with tumors enriched in a myeloid component.
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Affiliation(s)
- Diana Llopiz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Leyre Silva
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Marta Ruiz
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Carla Castro-Alejos
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Belen Aparicio
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
| | - Lucia Vegas
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
| | - Stefany Infante
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- DNA and RNA Medicine Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
- Facultad de Medicina Humana, Universidad de Piura, Lima, Peru
| | - Eva Santamaria
- DNA and RNA Medicine Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Pablo Sarobe
- Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, Spain
- Navarra Institute for Health Research (IDISNA), Pamplona, Spain
- CIBERehd, Pamplona, Spain
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Cao L, Shao M, Gu Y, Jia D, Lu W, Liang C, Liu X, Pan Z, Zhang Y, Hu J, Peng P. Calceolarioside B targets MMP12 in the tumor microenvironment to inhibit M2 macrophage polarization and suppress hepatocellular carcinoma progression. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 142:156805. [PMID: 40347889 DOI: 10.1016/j.phymed.2025.156805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 04/01/2025] [Accepted: 04/25/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are crucial in hepatocellular carcinoma (HCC) progression and prognosis, making them promising immunotherapy targets. In traditional Chinese medicine (TCM), qi stagnation and blood stasis are linked to the HCC tumor microenvironment (TME), but few studies explore the effects of related TCM herbs on the TME. Calceolarioside B, a key phenylethanoid glycoside in Akebiae Fructus, has not been well studied for its pharmacological activities or molecular targets, and its role in HCC remains unclear. PURPOSE This study aimed to investigate the effects of Calceolarioside B on TAMs in HCC and clarify its potential targets and regulatory mechanisms. METHODS Murine intrahepatic transplantation HCC models and macrophage-HCC cell co-culture systems were used to investigate the effects of Calceolarioside B on M2-like TAMs polarization and infiltration, and tumor growth. Cellular thermal shift assay, small molecular pull-down assay and surface plasmon resonance were utilized to identify the potential targets regulating M2-like TAMs. Single-cell RNA sequencing and TCGA dataset analyses clarified the differential expression, prognosis, and TAMs association of the potential targets in HCC. RESULTS Calceolarioside B reduces M2-like TAMs polarization and infiltration in the TME by binding to and inhibiting matrix metallopeptidase-12 (MMP12) form both macrophages and HCC cells, thereby preventing immunosuppressive effects. Public database analysis revealed that MMP12 overexpression promoted macrophage infiltration, with MMP12+ macrophages preferentially aggregating in primary and metastatic HCC tumors. CONCLUSION Calceolarioside B is identified as a novel MMP12 inhibitor modulating TAMs in the TME, offering a potential TAM-targeting strategy for HCC therapy.
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Affiliation(s)
- Linna Cao
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Miaomiao Shao
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yifei Gu
- Department of Orthopaedics, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Dongwei Jia
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wenli Lu
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Chao Liang
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaomei Liu
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhiqiang Pan
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Yiwei Zhang
- Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Jinquan Hu
- Department of Orthopaedics, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
| | - Peike Peng
- School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Cheng Z, Yang X, Ren Y, Wang H, Zhang Q, Lin S, Wu W, Yang X, Zheng J, Liu X, Tao X, Chen X, Qian Y, Li X. Investigating the molecular mechanisms and clinical potential of APO+ endothelial cells associated with PANoptosis in the tumor microenvironment of hepatocellular carcinoma using single-cell sequencing data. Transl Oncol 2025; 57:102402. [PMID: 40318262 DOI: 10.1016/j.tranon.2025.102402] [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: 02/24/2025] [Revised: 03/27/2025] [Accepted: 04/19/2025] [Indexed: 05/07/2025] Open
Abstract
INTRODUCTION PANoptosis is a newly identified form of programmed cell death that integrates elements of pyroptosis, apoptosis, and necroptosis. It plays a pivotal role in shaping the tumor immune microenvironment. Despite its significance, the specific functions and mechanisms of PANoptosis within the tumor microenvironment (TME) of hepatocellular carcinoma (HCC) remain unclear. This study aims to investigate these mechanisms using single-cell RNA sequencing data. METHODS Single-cell RNA sequencing data from HCC patients were obtained from the GEO database. The AUCell algorithm was used to quantify PANoptosis activity across various cell types in the TME. Cell populations with high PANoptosis scores were further analyzed using CytoTRACE and scMetabolism to assess their differentiation states and metabolic profiles. Associations between these high-score cell subsets and patient prognosis, tumor stage, and response to immunotherapy were examined. Cell-cell communication analysis was performed to explore how PANoptosis-related APO+ endothelial cells (ECs) may influence HCC progression. Immunofluorescence staining was used to assess the spatial distribution of APO+ ECs in tumor and adjacent tissues. Finally, a CCK8 assay was conducted to evaluate the effect of APOH+ HUVECs on HCC cell proliferation. RESULTS A total of 16 HCC patient samples with single-cell RNA sequencing data were included in the study. By calculating the PANoptosis scores of different cell types, we found that ECs, macrophages, hepatocytes, and fibroblasts exhibited higher PANoptosis scores. The PANoptosis scores, differentiation trajectories, intercellular communication, and metabolic characteristics of these four cell subpopulations with high PANoptosis scores were visualized. Among all subpopulations, APO+ ECs demonstrated the most significant clinical relevance, showing a positive correlation with better clinical staging, prognosis, and response to immunotherapy in HCC patients. Cellular communication analysis further revealed that APO+ ECs might regulate the expression of HLA molecules, thereby influencing T cell proliferation and differentiation, potentially contributing to improved prognosis in HCC patients. Immunofluorescence staining results indicated that APO+ ECs were primarily located in the adjacent tissues of HCC patients, with lower expression in tumor tissues. The results of cellular experiments showed that APOH+ HUVECs significantly inhibited the proliferation of HCC cells. CONCLUSIONS This study systematically mapped the cellular landscape of the TME in HCC patients and explored the differences in differentiation trajectories, metabolic pathways, and other aspects of subpopulations with high PANoptosis scores. Additionally, the study elucidated the potential molecular mechanisms through which APO+ ECs inhibit HCC cell proliferation and improve prognosis and immunotherapeutic efficacy in HCC patients. This research provides new insights for clinical prognosis evaluation and immunotherapy strategies in HCC.
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Affiliation(s)
- Zhaorui Cheng
- Department of Emergency, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China; Department of Urology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
| | - Xiangyu Yang
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, Yuzhong District, Chongqing, China.
| | - Yi Ren
- Southern University of Science and Technology, Shenzhen, Guangdong, China.
| | - Huimin Wang
- Department of Traditional Chinese Medicine, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China
| | - Qi Zhang
- Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China
| | - Sailing Lin
- Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China
| | - Wenhao Wu
- Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China
| | - Xiaolu Yang
- Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China
| | - Jiahan Zheng
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xinzhu Liu
- Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China
| | - Xin Tao
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, JiangXi, China
| | - Xiaoyong Chen
- Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, China.
| | - Yuxin Qian
- Department of Emergency, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China; Department of Urology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
| | - Xiushen Li
- Department of Traditional Chinese Medicine, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China; Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 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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Ye D, Zhang Z, Yao Y, Pan B, Wu H, Zhang X, Wang X, Tang N. Neurogranin facilitates maintaining the immunosuppressive state of hepatocellular carcinoma by promoting TGF-β1 secretion. Int J Biol Macromol 2025; 311:143716. [PMID: 40316076 DOI: 10.1016/j.ijbiomac.2025.143716] [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: 01/25/2025] [Revised: 04/27/2025] [Accepted: 04/29/2025] [Indexed: 05/04/2025]
Abstract
Immunotherapy has revolutionized cancer treatment, but its effectiveness is limited due to the complexity of the tumor immune microenvironment. Identifying reliable biomarkers that can predict immunotherapy response is essential for enhancing treatment strategies. This study evaluated the potential of Neurogranin (NRGN) as a biomarker for prognosis and immunotherapy response across multiple cancers. Through pan-cancer bioinformatics analyses, coupled with in vitro and in vivo experiments, we explored NRGN's differential expression across various cancer types and its role in the immune microenvironment. Our approach involved database mining, immune genomic feature correlation analyses, and functional validation through NRGN knockdown and overexpression studies. The results revealed differential NRGN expression across cancers, particularly hepatocellular carcinoma (HCC), where elevated levels correlated with immune evasion, poor prognosis, and upregulation of checkpoint genes like TGFB1. NRGN modulated T cell activity and macrophage polarization by regulating the TGF-β pathway through interaction with TCF4 and promoting its nuclear localization, driving tumor progression. Targeting TGF-β with anti-TGF-β and anti-PD-1 antibodies additively inhibited HCC in an Nrgn-dependent manner in mice. These findings indicate that NRGN may serve as a promising immunotherapeutic target, as its overexpression predicts poor prognosis and immune evasion, thereby offering insights for improving immunotherapy and developing new treatments.
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Affiliation(s)
- Dongjie Ye
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Zhu Zhang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Yuxin Yao
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Banglun Pan
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Hao Wu
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Xinyu Zhang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Xiaoqian Wang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China
| | - Nanhong Tang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China; Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
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Shao Y, Lu D, Jin W, Chen S, Han L, Wang T, Fu L, Yu H. Targeting LIF With Cyclovirobuxine D to Suppress Tumor Progression via LIF/p38MAPK/p62-Modulated Mitophagy in Hepatocellular Carcinoma. MedComm (Beijing) 2025; 6:e70227. [PMID: 40416597 PMCID: PMC12103653 DOI: 10.1002/mco2.70227] [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: 08/27/2024] [Revised: 03/27/2025] [Accepted: 03/31/2025] [Indexed: 05/27/2025] Open
Abstract
Leukemia inhibitory factor (LIF) exerts an oncogenic function in several types of cancer, including hepatocellular carcinoma (HCC). However, small-molecule inhibitors of LIF haven't been established. Here, we identified that LIF was remarkably overexpressed in HCC by multi-omics approaches, indicating that inhibition of LIF would be a promising therapeutic strategy. Inhibiting LIF could suppress proliferation and metastasis by activating p38MAPK/p62-modulated mitophagy. Interestingly, we found that the natural small-molecule Cyclovirobuxine-D (CVB-D), was a new inhibitor of cytoplasmic LIF in HCC. We further validated LIF as a potential target of CVB-D through biotin-modified CVB-D-Probe utilizing mass spectrometry. Mechanistically, we showed that CVB-D could bind to LIF at Val145, thereby inducing mitophagy, accompanied by cell cycle arrest and inhibition of invasion and migration. Moreover, we demonstrated that CVB-D had a therapeutic potential by targeting LIF-modulated mitophagy in patient-derived xenograft (PDX) models, which would elucidate LIF as a druggable target and regulatory mechanisms and exploit CVB-D as the novel small-molecule inhibitor of LIF for future HCC drug discovery.
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Affiliation(s)
- Yingying Shao
- State Key Laboratory of Chinese Medicine ModernizationTianjin University of Traditional Chinese MedicineTianjinChina
- School of MedicineNankai UniversityTianjinChina
| | - Di Lu
- Affiliated Hangzhou First People's HospitalZhejiang University School of MedicineHangzhouChina
| | - Wenke Jin
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural DrugsSchool of Life Science and EngineeringSouthwest Jiaotong UniversityChengduChina
| | - Sibao Chen
- State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation)Shenzhen, Department of Applied Biology and Chemical TechnologyResearch Center for Chinese Medicine InnovationThe Hong Kong Polytechnic UniversityHong KongChina
| | - Lifeng Han
- State Key Laboratory of Chinese Medicine ModernizationTianjin University of Traditional Chinese MedicineTianjinChina
- Haihe Laboratory of Modern Chinese MedicineTianjinChina
| | - Tao Wang
- State Key Laboratory of Chinese Medicine ModernizationTianjin University of Traditional Chinese MedicineTianjinChina
- Haihe Laboratory of Modern Chinese MedicineTianjinChina
| | - Leilei Fu
- Department of BiotherapyCancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural DrugsSchool of Life Science and EngineeringSouthwest Jiaotong UniversityChengduChina
| | - Haiyang Yu
- State Key Laboratory of Chinese Medicine ModernizationTianjin University of Traditional Chinese MedicineTianjinChina
- Haihe Laboratory of Modern Chinese MedicineTianjinChina
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Sangro B, Argemí J. MORPHEUS-Liver provides a way forward in expanding the immunotherapy options for hepatocellular carcinoma. Nat Rev Clin Oncol 2025; 22:383-384. [PMID: 40065095 DOI: 10.1038/s41571-025-01009-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2025]
Affiliation(s)
- Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra, Pamplona, Spain.
- CIBEREHD, Instituto de Salud Carlos III, Madrid, Spain.
| | - Josepmaria Argemí
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra, Pamplona, Spain
- CIBEREHD, Instituto de Salud Carlos III, Madrid, Spain
- RNA and DNA Medicine Program, Center for Applied Medical Research (CIMA), Pamplona, Spain
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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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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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10
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Yang A, Zhou M, Gao Y, Zhang Y. Mechanisms of CD8 + T cell exhaustion and its clinical significance in prognosis of anti-tumor therapies: A review. Int Immunopharmacol 2025; 159:114843. [PMID: 40394796 DOI: 10.1016/j.intimp.2025.114843] [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: 12/09/2024] [Revised: 05/05/2025] [Accepted: 05/08/2025] [Indexed: 05/22/2025]
Abstract
In recent years, immunotherapy has gradually become one of the main strategies for cancer treatment, with immune checkpoint inhibitors (ICIs) offering new possibilities for tumor therapy. However, some cancer patients exhibit low responses and resistance to ICIs treatment. T cell exhaustion, a process associated with tumor progression, refers to a subset of T cells that progressively lose effector functions and exhibit increased expression of inhibitory receptors. These exhausted T cells are considered key players in the therapeutic efficacy of immune checkpoint inhibitors. Therefore, understanding the impact of T cell exhaustion on tumor immunotherapy and the underlying mechanisms is critical for improving clinical treatment outcomes. Several elegant studies have provided insights into the prognostic value of exhausted T cells in cancers. In this review, we highlight the process of exhausted T cells and its predictive value in various cancers, as well as the relevant mechanisms behind it, providing new insights into the immunotherapy of cancer.
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Affiliation(s)
- Anrui Yang
- Department of Gynecological Minimal Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Meng Zhou
- Department of Gynecological Minimal Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Yixuan Gao
- Department of Gynecological Minimal Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Ying Zhang
- Department of Gynecological Minimal Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
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11
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Dai W, Li Y, Wu S, Wang Q, Zheng X, Zhang J, Han X, Zhou Y. Identification of MAGE-A10 specific T cell receptor promising in immunotherapy of hepatocellular carcinoma. Int J Biol Macromol 2025; 315:144243. [PMID: 40379175 DOI: 10.1016/j.ijbiomac.2025.144243] [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: 03/20/2025] [Revised: 05/12/2025] [Accepted: 05/13/2025] [Indexed: 05/19/2025]
Abstract
Due to the limitations of current treatment strategies, hepatocellular carcinoma (HCC) continues to impose a severe burden on people's health. In the process of exploring novel therapies, T cell receptor-engineered T cell (TCR-T) therapy has been extensively developed in HCC immunotherapy. Melanoma-associated antigen family A member 10 (MAGE-A10) is a cancer-testis antigen (CTA), specifically expressed on HCC cells. However, the identification of TCR-T targeting MAGE-A10 in HCC remains rarely discussed. In this study, single-cell RNA sequencing (scRNA-seq) and TCR sequencing (scTCR-seq) were performed on samples from HCC patients. The cellular landscape of HCC was illustrated through a single-cell atlas. Reactive T cells were defined based on the matched T cells. Additionally, most reactive T cells were enriched in CD4_CD69_Th, CD4_FOXP3_Treg, CD4_CXCL13_TEX, and CD8_CXCL13_TEX. GLIPH2 was utilized to cluster TCRs from reactive T cells, enabling the identification of reactive TCRs. TCRMatch predicted MAGE-A10 as a specific antigen recognized by one of the reactive TCRs. Furthermore, the affinity assessments between human leukocyte antigen (HLA), epitope of MAGE-A10, and the identified TCR were performed with NetMHCpan and DLpTCR. Finally, cytotoxicity assays indicated the specific recognition and killing of MAGE-A10-TCR-T cells against HCC cells, paving the way for TCR-T immunotherapy in HCC.
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Affiliation(s)
- Wei Dai
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China; Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Yuanqi Li
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China; Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Shaoxian Wu
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China; Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Qi Wang
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China; Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Xiao Zheng
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China; Institute of Cell Therapy, Soochow University, Changzhou 213003, China
| | - Jinping Zhang
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
| | - Xiao Han
- Institute of Pediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangzhou 510623, China.
| | - You Zhou
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China; Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou 213003, China; Institute of Cell Therapy, Soochow University, Changzhou 213003, China.
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12
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Yang R, Wang H, Wu C, Shi Y, Li H, Bao X, Yang Y, Han S, Yang X, Tao J, Sun H, Wu S, Sun L. PAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-κB signaling. Biomark Res 2025; 13:70. [PMID: 40336138 PMCID: PMC12060467 DOI: 10.1186/s40364-025-00785-z] [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: 10/29/2024] [Accepted: 04/26/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Progesterone and adipose Q receptor 5 (PAQR5), a membrane receptor characterized by seven transmembrane domains, has been indirectly implicated in pro-carcinogenic activities, though its specific role in hepatocellular carcinoma (HCC) remains to be defined. METHODS This study aimed to elucidate the molecular mechanisms by which PAQR5 facilitates HCC progression and contributes to the immunosuppressive microenvironment through an integrative approach combining multi-omics analysis and experimental validation. Utilizing data from bulk, single-cell, and spatial transcriptomics cohorts, this study systematically assessed the expression patterns, immune landscape, and functional characteristics of PAQR5 across different levels of resolution in HCC. RESULTS PAQR5 expression was significantly upregulated in tumor tissues and correlated with poor clinical outcomes. Enrichment analysis revealed that PAQR5 activated the NF-κB signaling pathway in HCC. Single-cell transcriptomics identified PAQR5 as predominantly localized within malignant cell clusters, with significant association with NF-κB pathway activation. Spatial transcriptomics further corroborated the alignment of PAQR5 expression with tumor cell distribution. In vitro assays showed elevated PAQR5 levels in HCC cell lines, and silencing PAQR5 significantly suppressed cell proliferation, invasion, epithelial-mesenchymal transition (EMT), and prevented the formation of immunosuppressive microenvironment. In vivo studies demonstrated that targeting PAQR5 attenuated tumorigenic potential, disrupted the invasion-metastasis cascade and inhibited the tumor immune escape. Mechanistically, PAQR5 was found to activate NF-κB signaling by inducing ERK phosphorylation, thereby driving proliferation, invasion, EMT, and immune escape in HCC through the pathway.
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Affiliation(s)
- Ruida Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
- Department of Thoracic Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huanhuan Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Cong Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Yu Shi
- Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Hanqi Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Xinyue Bao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Yuqian Yang
- Department of Medical Oncology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 711018, Shaanxi, People's Republic of China
| | - Shaoshan Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Xue Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Jie Tao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Hao Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
| | - Shaobo Wu
- Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
| | - Liankang Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
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13
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Tong J, Tan Y, Ouyang W, Chang H. Targeting immune checkpoints in hepatocellular carcinoma therapy: toward combination strategies with curative potential. Exp Hematol Oncol 2025; 14:65. [PMID: 40317077 PMCID: PMC12046748 DOI: 10.1186/s40164-025-00636-5] [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: 01/20/2025] [Accepted: 03/07/2025] [Indexed: 05/04/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by poor immune cell infiltration and a strongly immunosuppressive microenvironment. Traditional treatments have often yielded unsatisfactory outcomes due to the insidious onset of the disease. Encouragingly, the introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the approach to HCC treatment. Moreover, combining ICIs with other therapies or novel materials is considered the most promising opportunity in HCC, with some of these combinations already being evaluated in large-scale clinical trials. Unfortunately, most clinical trials fail to meet their endpoints, and the few successful ones also face challenges. This indicates that the potential of ICIs in HCC treatment remains underutilized, prompting a reevaluation of this promising therapy. Therefore, this article provides a review of the role of immune checkpoints in cancer treatment, the research progress of ICIs and their combination application in the treatment of HCC, aiming to open up avenues for the development of safer and more efficient immune checkpoint-related strategies for HCC treatment.
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Affiliation(s)
- Jing Tong
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Yongci Tan
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Wenwen Ouyang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China
| | - Haocai Chang
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China.
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, School of Optoelectronic Science and Engineering, South China Normal University, Guangzhou, 510631, China.
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14
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Gao S, Fan L, Wang H, Wang A, Hu M, Zhang L, Sun G. NCOA5 induces sorafenib resistance in hepatocellular carcinoma by inhibiting ferroptosis. Cell Death Discov 2025; 11:215. [PMID: 40316542 PMCID: PMC12052255 DOI: 10.1038/s41420-025-02473-1] [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: 08/13/2024] [Revised: 03/26/2025] [Accepted: 04/02/2025] [Indexed: 05/04/2025] Open
Abstract
NCOA5 has been identified as a crucial factor in the progression of hepatocellular carcinoma (HCC). This study investigates the expression of NCOA5 in HCC, revealing its significant overexpression in tumor tissues compared to healthy liver tissues, as evidenced by analysis of the TCGA dataset and RT-qPCR in patient samples. Higher NCOA5 levels correlate with poor overall survival, highlighting its role as a prognostic indicator. Furthermore, our findings suggest that elevated NCOA5 is associated with resistance to sorafenib, a common chemotherapeutic agent for HCC, as shown through analysis of publicly available datasets and the establishment of sorafenib-resistant HCC cell lines. Mechanistically, NCOA5 appears to inhibit ferroptosis in HCC cells by modulating glutathione peroxidase 4 (GPX4) levels. Knockdown of NCOA5 sensitizes resistant cell lines to sorafenib and induces ferroptosis by decreasing GPX4 expression. Additionally, NCOA5 regulation of GPX4 is mediated through the transcription factor MYC. In vivo studies further validate that targeting NCOA5 enhances the efficacy of sorafenib in resistant HCC models by promoting ferroptosis. Collectively, these findings underscore the potential of NCOA5 as a therapeutic target to overcome drug resistance in HCC, providing insights into its role in modulating treatment responses and patient prognosis.
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Affiliation(s)
- Shuang Gao
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Lulu Fan
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Huiyan Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230001, China
| | - Anqi Wang
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Mengyao Hu
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Lei Zhang
- Department of General Surgery, The Second Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233080, China.
| | - Guoping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230001, China.
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15
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Xiao K, Li K, Xiao K, Yang J, Zhou L. Gut Microbiota and Hepatocellular Carcinoma: Metabolic Products and Immunotherapy Modulation. Cancer Med 2025; 14:e70914. [PMID: 40314129 PMCID: PMC12046294 DOI: 10.1002/cam4.70914] [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: 01/16/2025] [Revised: 03/31/2025] [Accepted: 04/16/2025] [Indexed: 05/03/2025] Open
Abstract
BACKGROUND The relationship between hepatocellular carcinoma (HCC) and gut microbiota has gained attention for its impact on HCC immunotherapy. METHODS Key gut microbial metabolites, including bile acids, toll-like receptor 4, short-chain fatty acids, and bacterial toxins, contribute to HCC progression and influence immune responses through the gut-liver axis. As immune checkpoint inhibitors (ICIs) become common in HCC treatment, modulating the gut microbiota offers new strategies to enhance ICIs efficacy. However, individual differences in microbial composition introduce challenges, with some HCC patients showing resistance to ICIs. RESULTS This review summarizes the latest findings on the role of gut microbiota in HCC and explores emerging therapeutic approaches, including fecal microbiota transplantation, probiotics, antibiotics, and natural compounds. CONCLUSIONS The focus is on translating these insights into personalized medicine to optimize ICIs responses and improve HCC treatment outcomes.
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Affiliation(s)
- Kunmin Xiao
- Department of OncologyLonghua Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Kexin Li
- Department of Traditional Chinese MedicinePeking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical ScienceBeijingChina
| | - Kunlin Xiao
- Department of EmergencyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Jinzu Yang
- Department of OncologyLonghua Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Lei Zhou
- Department of OncologyLonghua Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChina
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16
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Li Y, Wang X, Ye F, Hong X, Chen Y, Huang J, Liu J, Huang X, Liang L, Guo Y, Shi F, Zhu K, Lin L, Huang W. Acid-responsive engineered bacteria with aberrant In-Situ anti-PD-1 expression for post-ablation immunotherapy of hepatocellular carcinoma. Biomed Pharmacother 2025; 186:118046. [PMID: 40209305 DOI: 10.1016/j.biopha.2025.118046] [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: 10/06/2024] [Revised: 03/20/2025] [Accepted: 04/03/2025] [Indexed: 04/12/2025] Open
Abstract
Local thermal ablation (TA) can not only reduce the tumor burden of hepatocellular carcinoma (HCC) but also stimulate the host anti-tumor immune response, offering a promising avenue for combination with immune checkpoint blockade (ICB). However, tumor recurrence and ICB resistance are associated with residual tumor masses caused by incomplete TA treatment. Thus, adjuvant therapy that can accurately eliminate residual HCC tumors post-TA is expected to improve prognosis. Bacteria-mediated tumor therapy has showed promising potential for tumor-targeting ability and in situ therapeutic proteins expression in the tumor. Here, we presented a kind of nonpathogenic engineered bacteria (named PD-1@EcM) for the potent tumor-targeting and acidic-controlled production of fusion protein comprising a mouse-derived anti-PD-1 single-chain variable fragment (scFv). A single injection of this engineered bacteria demonstrated a significantly tumor inhibition and extended survival in advanced murine primary and metastatic post-TA treatment HCC model. We observed that this engineered bacteria elicited an enhanced antitumour immune response resulting in an extensive priming of activated CD8+ T cells and polarization of tumor-associated macrophage from M2 phenotype to M1 phenotype. Taken together, this work provides a novel strategy to address major challenges in TA therapy and expand the current applications of bacteria-based platforms for precision therapy.
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Affiliation(s)
- Yue Li
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China
| | - Xiaobin Wang
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China
| | - Feilong Ye
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China
| | - Xiaoyang Hong
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China
| | - Ye Chen
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China
| | - Jiabai Huang
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China
| | - Jianxin Liu
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China
| | - Xinkun Huang
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China
| | - Licong Liang
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China
| | - Yongjian Guo
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China
| | - Feng Shi
- Department of Interventional Radiology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern medical university, Guangzhou, China
| | - Kangshun Zhu
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China.
| | - Liteng Lin
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China.
| | - Wensou Huang
- Laboratory of Interventional Radiology, Department of Minimally Invasive Interventional Radiology and Department of Radiology, The Second Affiliated Hospital, Guangzhou Medical University, Changgangdong Road, Haizhu District, Guangzhou, Guangdong Province 510261, China.
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17
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Guo X, Cui T, Sun L, Fu Y, Cheng C, Wu C, Zhu Y, Liang S, Liu Y, Zhou S, Li X, Ji C, Ma K, Zhang N, Chu Q, Xing C, Deng S, Wang J, Liu Y, Liu L. A STT3A-dependent PD-L1 glycosylation modification mediated by GMPS drives tumor immune evasion in hepatocellular carcinoma. Cell Death Differ 2025; 32:944-958. [PMID: 39690246 DOI: 10.1038/s41418-024-01432-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 12/01/2024] [Accepted: 12/05/2024] [Indexed: 12/19/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor characterized by rapid progression. To explore the regulatory mechanism of rapid tumor growth and metastasis, we conducted proteomic and scRNA-Seq analyses on advanced HCC tissues and identified a significant molecule, guanine monophosphate synthase (GMPS), closely associated with the immune evasion in HCC. We analyzed the immune microenvironment characteristics remodeled by GMPS using scRNA-Seq and found GMPS induced tumor immune evasion in HCC by impairing the tumor-killing function of CD8 + T cells. Further investigation revealed that GMPS increased PD-L1 expression by regulating its ubiquitination and glycosylation modification. Mechanistically, GMPS enhanced the bond between PD-L1 and the catalytic subunit STT3A of oligosaccharyltransferase (OST) by acting as an additional module connecting the Sec61 channel complex and STT3A, which aided in the translocation and modification of nascent peptides. Increased PD-L1 impaired the tumor-killing function of CD8 + T cells, leading to the immune evasion. Importantly, targeting GMPS with angustmycin A, an inhibitor of GMPS activity, significantly suppressed PD-L1 expression and tumor growth in HCC, which also increased the sensitivity to anti-CTLA-4 immunotherapy. These findings suggested the potential of targeting GMPS as a promising therapeutic approach for HCC.
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Affiliation(s)
- Xinyu Guo
- Department of Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Tianming Cui
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Linmao Sun
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Yumin Fu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Cheng Cheng
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Chenghui Wu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Yitong Zhu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Shuhang Liang
- Department of Gastrointestinal Surgery, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Yufeng Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Shuo Zhou
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Xianying Li
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Changyong Ji
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Kun Ma
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Ning Zhang
- Department of Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Qi Chu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Changjian Xing
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Shumin Deng
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Jiabei Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China.
| | - Yao Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China.
| | - Lianxin Liu
- Department of Hepatic Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
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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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Zhang J, Guo J, Qian Y, Yu L, Ma J, Gu B, Tang W, Li Y, Li H, Wu W. Quercetin Induces Apoptosis Through Downregulating P4HA2 and Inhibiting the PI3K/Akt/mTOR Axis in Hepatocellular Carcinoma Cells: An In Vitro Study. Cancer Rep (Hoboken) 2025; 8:e70220. [PMID: 40347062 PMCID: PMC12065022 DOI: 10.1002/cnr2.70220] [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: 09/28/2024] [Revised: 03/25/2025] [Accepted: 04/22/2025] [Indexed: 05/12/2025] Open
Abstract
BACKGROUND Quercetin is a natural product with multiple activities, which possesses a promising antitumor effect on malignancies. The involvement of proline 4-hydroxylase II (P4HA2) in collagen synthesis is crucial in the growth of tumor cells. Apoptosis is a programmed cell death requisite for the stability of the intracellular environment. However, the relationship between quercetin and cell apoptosis, as well as the impact of P4HA2 in this connection, has not yet been specified in hepatocellular carcinoma(HCC). AIMS The present study used HCC cells to investigate how quercetin regulates P4HA2 and influences cell proliferation and apoptosis. METHODS AND RESULTS The outcomes reveal that quercetin can impede the viability and growth of HCC cells and generate cell apoptosis in a dose-dependent manner. Additionally, quercetin prompts downregulation of P4HA2, leading to cell apoptosis in HCC cells, and knocking down P4HA2 can enhance this effect. Furthermore, we pretreated HCC cells with inhibitors (Z-VAD-FMK, LY294002) or activators (740Y-P) and found that the PI3K/Akt/mTOR pathway was occupied with quercetin-induced cell apoptosis. CONCLUSION This investigation reveals that quercetin compels apoptosis in HCC cells by diminishing P4HA2 and restraining the PI3K/Akt/mTOR axis.
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Affiliation(s)
- Junli Zhang
- The Third People's Hospital of Bengbu Affiliated to Bengbu Medical UniversityBengbuChina
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and TreatmentBengbuChina
- Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory DiagnosisBengbu Medical UniversityBengbuChina
| | - Jiayi Guo
- Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory DiagnosisBengbu Medical UniversityBengbuChina
| | - Ying Qian
- Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory DiagnosisBengbu Medical UniversityBengbuChina
| | - Lianchen Yu
- Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory DiagnosisBengbu Medical UniversityBengbuChina
| | - Junrao Ma
- Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory DiagnosisBengbu Medical UniversityBengbuChina
| | - Biao Gu
- The Third People's Hospital of Bengbu Affiliated to Bengbu Medical UniversityBengbuChina
| | - Weichun Tang
- The Third People's Hospital of Bengbu Affiliated to Bengbu Medical UniversityBengbuChina
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and TreatmentBengbuChina
| | - Yi Li
- The Third People's Hospital of Bengbu Affiliated to Bengbu Medical UniversityBengbuChina
| | - Hongwei Li
- The Third People's Hospital of Bengbu Affiliated to Bengbu Medical UniversityBengbuChina
| | - Wenjuan Wu
- Bengbu Medical University Key Laboratory of Cancer Research and Clinical Laboratory DiagnosisBengbu Medical UniversityBengbuChina
- Department of Biochemistry and Molecular BiologySchool of Laboratory Medicine, Bengbu Medical UniversityBengbuChina
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20
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Qiu Y, Xu J, Liao W, Yang S, Wen Y, Farag MA, Zheng L, Zhao C. Ulvan derived from Ulva lactuca suppresses hepatocellular carcinoma cell proliferation through miR-542-3p-mediated downregulation of SLC35F6. Int J Biol Macromol 2025; 308:142252. [PMID: 40118430 DOI: 10.1016/j.ijbiomac.2025.142252] [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: 12/12/2024] [Revised: 03/13/2025] [Accepted: 03/16/2025] [Indexed: 03/23/2025]
Abstract
Hepatocellular carcinoma (HCC) therapy still presents significant challenges, with a critical need for novel molecular targets and effective natural compound-based therapies. Despite its known oncogenic potential in other cancers, the role of SLC35F6 in HCC has not been previously reported, leaving a gap in our understanding of its function and therapeutic relevance. Here, we demonstrate that SLC35F6 is overexpressed in HCC and is associated with poor prognosis. Ulva lactuca polysaccharide (ULP), a natural extract with known antitumor properties, exerts its effects by upregulating miR-542-3p, which in turn inhibits SLC35F6 expression and significantly increases TP53 protein levels. Furthermore, TP53 is positively regulated by miR-542-3p, and our results indicate that SLC35F6 is a target gene of miR-542-3p. Knockdown of SLC35F6 in H22 and HepG2 cells markedly reduced cell growth while elevating TP53 expression, supporting SLC35F6 as a key regulatory factor in the miR-542-3p/TP53 axis. While this study did not confirm direct mutual regulation between SLC35F6 and TP53, our findings provide evidence that targeting SLC35F6 can suppress HCC progression. Collectively, these results identify SLC35F6 as a potential therapeutic target for HCC and provide mechanistic insights into its regulation through the miR-542-3p/SLC35F6/TP53 axis.
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Affiliation(s)
- Yinghui Qiu
- College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; School of Materials Science and Engineering, Huaqiao University, Xiamen 361021, China
| | - Jingxiang Xu
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Wei Liao
- State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, Fujian Agriculture and Forestry University, Fuzhou 350002, China; State Key Laboratory of Food Science and Resources, China-Canada Joint Lab of Food Science and Technology, Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang 330047, China
| | - Shuxin Yang
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Yuxi Wen
- University of Vigo, Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Science, E32004 Ourense, Spain
| | - Mohamed A Farag
- Pharmacognosy Department, College of Pharmacy, Cairo University, Cairo, Egypt
| | - Lingjun Zheng
- School of Agriculture and Biology, Shanghai JiaoTong University, Shanghai 200240, China
| | - Chao Zhao
- College of Marine Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; State Key Laboratory of Mariculture Breeding, Key Laboratory of Marine Biotechnology of Fujian Province, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
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21
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Chen H, Xiao Z, Lu Z, Xu N, Wei Q, Xu X. Targeted activation of junctional adhesion molecule-like protein + CD8 + T cells enhances immunotherapy in hepatocellular carcinoma. Chin J Cancer Res 2025; 37:212-226. [PMID: 40353078 PMCID: PMC12062980 DOI: 10.21147/j.issn.1000-9604.2025.02.08] [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: 09/11/2024] [Accepted: 03/24/2025] [Indexed: 05/14/2025] Open
Abstract
Objective Cytotoxic T lymphocytes (CTLs) play a crucial role in the therapeutic approach to hepatocellular carcinoma (HCC). Recent research has indicated that junctional adhesion molecule-like protein (JAML) enhances the antitumor activity of CD8+ T cells. Our study investigates the role of JAML+ CD8+ T cells in HCC. Methods We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy. Flow cytometry was used to assess CD4+ T cells differentiation and JAML expression in CD8+ T cells infiltrating HCC. Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+ (LDHA+) CD4+ T cells and JAML+ CD8+ T cells. Subsequently, we evaluated the therapeutic effects of an agonistic anti-JAML antibody, both alone and combined with immunotherapy. Finally, RNA sequencing was conducted to identify potential regulatory mechanisms. Results Immunotherapy significantly increased the percentage of CD8+ T cells infiltrating HCC and induced histone modifications, such as H3K18 lactylation (H3K18la) in CD4+ T cells. Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+ T cells into Th1 cells. LDHA, an enzyme that converts pyruvate to lactate, plays a key role in this process. Correlation analysis revealed a strong positive relationship between LDHA+ CD4+ T cells and JAML+ CD8+ T cells in patients who responded to immunotherapy. Moreover, high JAML expression in CD8+ T cells was associated with a more favorable prognosis. In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice, independent of the effects of anti-programmed cell death protein ligand-1 antibody (αPD-L1)-mediated immunotherapy. Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway. Conclusions Activation of JAML enhances CTL responses in HCC treatment, independent of αPD-L1-mediated immunotherapy, providing a promising strategy for advanced HCC.
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Affiliation(s)
- Huan Chen
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Zhaofeng Xiao
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Zhengyang Lu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Nan Xu
- Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Qiang Wei
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310053, China
| | - Xiao Xu
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310053, China
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22
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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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23
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Wang X, Liu D, Wang S, He R. An immune cell activation signature reflected hepatocellular carcinoma heterogeneity and predicted clinical outcomes. Front Immunol 2025; 16:1534611. [PMID: 40356904 PMCID: PMC12066757 DOI: 10.3389/fimmu.2025.1534611] [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] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 04/01/2025] [Indexed: 05/15/2025] Open
Abstract
Background The prognosis of hepatocellular carcinoma (HCC) remains challenging, and immune activation plays a critical role in cancer treatment. Identifying reliable immune activation-related prognostic markers is critical for predicting HCC patient outcomes. Method A six-gene signature was developed. The prognostic value was assessed by correlating the signature and survival. The robustness of the signature was validated in three independent Gene Expression Omnibus (GEO) datasets. Associations with clinical, genomic, and transcriptomic features were also evaluated. Additionally, single-cell sequencing data were analyzed to explore cell-cell interaction heterogeneity reflected by the signature. The biological role of candidate gene RORC was investigated, including chemotherapy resistance and detailed regulatory mechanism in affecting progression. The clinical potential role of RORC and its downstream gene was also evaluated by immunohistochemical (IHC) microarray. Results The six-gene signature stratified patients into high-risk and low-risk groups, with high-risk samples exhibiting significantly shorter overall survival (median: 23.8 months, 95% CI: 20.6-41.8) than low-risk samples (median: 83.2 months, 95% CI: 69.6-NA, p < 0.001). Validation in independent GEO datasets confirmed the robustness of the signature. The signature was significantly associated with the pathological stage and negatively correlated with PD-L1 expression, outperforming clinical indicators in predicting 3-year survival. The signature was significantly associated with TP53 mutations, genomic stability, and canonical cancer-related pathways. Single-cell sequencing data indicated that the signature revealed cell-cell interaction heterogeneity in HCC. Candidate gene RORC promotes proliferation and migration by regulating CDC6 gene expression as a transcription factor. Furthermore, RORC is also associated with multiple drug resistance, especially docetaxel and paclitaxel. IHC revealed that RORC and candidate gene CDC6 were valuable predictive biomarkers for prognosis. Conclusion The six-gene signature provides valuable insights into the biological status of HCC patients and is a robust tool for clinical application.
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Affiliation(s)
- Xiaofeng Wang
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ;China
| | - Dongli Liu
- Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ;China
| | - Shuai Wang
- Department of Radiation, Chushi Orthopedic Hospital, Zhengzhou, Henan, ;China
| | - Rui He
- Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, ;China
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24
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Wang W, Gao X, Niu W, Yin J, He K. Targeting Metabolism: Innovative Therapies for MASLD Unveiled. Int J Mol Sci 2025; 26:4077. [PMID: 40362316 PMCID: PMC12071536 DOI: 10.3390/ijms26094077] [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: 02/22/2025] [Revised: 04/01/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.
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Affiliation(s)
- Weixin Wang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Xin Gao
- School of Public Health, Jilin University, Changchun 130021, China;
| | - Wentong Niu
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
| | - Jinping Yin
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun 130041, China;
| | - Kan He
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (W.W.); (W.N.)
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25
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Wang PX, Zhong YC, Duan B, Cheng JW, Sun YF, Zheng WJ, Zhou KQ, Xu Y, Peng HX, Jin WX, Li HM, Sun XJ, Guo W, Zhou J, Liu Q, Fan J, Yang XR. Exploring morphological heterogeneity of circulating tumor cells: machine learning-based approach for cell identification and prognostic implications. Sci Bull (Beijing) 2025:S2095-9273(25)00433-5. [PMID: 40348669 DOI: 10.1016/j.scib.2025.04.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 12/28/2024] [Accepted: 03/31/2025] [Indexed: 05/14/2025]
Affiliation(s)
- Peng-Xiang Wang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Yu-Chen Zhong
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Bin Duan
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Bioinformatics Department, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Jian-Wen Cheng
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Yun-Fan Sun
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Wen-Jing Zheng
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Kai-Qian Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Yang Xu
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | | | | | - Hai-Min Li
- Dunwill Med-Tech, Shanghai 200032, China
| | | | - Wei Guo
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jian Zhou
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China
| | - Qi Liu
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Bioinformatics Department, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
| | - Jia Fan
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
| | - Xin-Rong Yang
- Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
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26
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Zhou L, Liu CH, Lv D, Sample KM, Rojas Á, Zhang Y, Qiu H, He L, Zheng L, Chen L, Cai B, Hu Y, Romero-Gómez M. Halting hepatocellular carcinoma: Identifying intercellular crosstalk in HBV-driven disease. Cell Rep 2025; 44:115457. [PMID: 40163359 DOI: 10.1016/j.celrep.2025.115457] [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: 09/20/2024] [Revised: 01/14/2025] [Accepted: 03/04/2025] [Indexed: 04/02/2025] Open
Abstract
Hepatitis B infection can lead to liver fibrosis and hepatocellular carcinoma (HCC). Despite antiviral therapies, some patients still develop HCC. This study investigates hepatitis B virus (HBV)-induced hepatocyte-hepatic stellate cell (HSC) crosstalk and its role in liver fibrosis and HCC. Using MYC-driven liver cancer stem cell organoids, HCC-patient-derived xenograft (PDX) models, and HBV replication models, this study reveals that HBV transcription affected hepatocyte development, activated the DNA repair pathway, and promoted glycolysis. HBV activated nicotinamide phosphoribosyltransferase (NAMPT) through DNA damage receptor ATR. NAMPT-insulin receptor (INSR)-mediated hepatocyte-HSC crosstalk caused HSCs to develop a myofibroblast phenotype and activated telomere maintenance mechanisms via PARP1 multisite lactylation. Inhibition of the ATR-NAMPT-INSR-PARP1 pathway effectively blocks HBV-induced liver fibrosis and HCC progression. Targeting this pathway could be a promising strategy for chronic HBV infection management.
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Affiliation(s)
- Lingyun Zhou
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China.
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Duoduo Lv
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Klarke Michael Sample
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Ángela Rojas
- SeLiver Group, Institute of Biomedicine of Seville (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
| | - Yugu Zhang
- Thoracic Oncology Ward, Cancer Center, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Huandi Qiu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Linye He
- Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China
| | - Li Zheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Liyu Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Binru Cai
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
| | - Yiguo Hu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China; Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China.
| | - Manuel Romero-Gómez
- SeLiver Group, Institute of Biomedicine of Seville (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain.
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27
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Fu X, Guo Y, Zhang K, Cheng Z, Liu C, Ren Y, Miao L, Liu W, Jiang S, Zhou C, Su Y, Yang L. Prognostic impact of extracellular volume fraction derived from equilibrium contrast-enhanced CT in HCC patients receiving immune checkpoint inhibitors. Sci Rep 2025; 15:13643. [PMID: 40254627 PMCID: PMC12009984 DOI: 10.1038/s41598-025-97677-x] [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: 01/06/2025] [Accepted: 04/07/2025] [Indexed: 04/22/2025] Open
Abstract
This study aimed to investigate whether extracellular volume (ECV) fraction derived from equilibration contrast-enhanced computed tomography (CECT) affects prognosis in HCC patients receiving ICIs. This retrospective study ultimately included 211 HCC patients undergoing ICIs, of whom 60 were included in an internal validation to assess the reproducibility of the results. Baseline unenhanced and equilibrated CECT were used to measure CT values of the tumor, liver and aorta, which were combined with hematocrit to calculate the ECV fraction. Correlation analysis was used to investigate the association between tumor ECV and liver ECV fractions. The effects of clinical variables and ECV fraction on progression-free survival (PFS) and overall survival (OS) were evaluated using Cox proportional hazards models and Kaplan-Meier curves. Of these 151 patients, tumor ECV fraction positively correlated with liver ECV fraction. In the Lower tumor ECV group, PFS (5.6 vs. 7.6 months) and OS (10.5 vs. 15.5 months) were notably shorter than in the Higher tumor ECV group, while no significant differences were found between the Higher and Lower liver ECV groups. Furthermore, the multivariable Cox regression model demonstrated that higher tumor ECV fraction level was an independent protective factor for PFS and OS (all P < 0.001). Internal validation cohort preliminary demonstrated reproducibility of results. The tumor ECV fraction is expected to become a routine indicator before ICIs therapy for HCC patients in contrast to liver ECV fraction, contributing to their subsequent management.
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Affiliation(s)
- Xiaona Fu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yusheng Guo
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Kailu Zhang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Zhixuan Cheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chanyuan Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yi Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Lianwei Miao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Weiwei Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Shanshan Jiang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| | - Yangbo Su
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
| | - Lian Yang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
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Shen D, Sha L, Yang L, Gu X. Based on disulfidptosis, unveiling the prognostic and immunological signatures of Asian hepatocellular carcinoma and identifying the potential therapeutic target ZNF337-AS1. Discov Oncol 2025; 16:544. [PMID: 40244531 PMCID: PMC12006654 DOI: 10.1007/s12672-025-02325-5] [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: 09/28/2024] [Accepted: 04/07/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Disulfidptosis is a newly discovered programmed cell death pathway that may be connected to tumorigenesis and development, showing promise as a novel treatment strategy for cancer. This study aims to construct a prognostic model of disulfidptosis-related Long non-coding RNAs (DRLRs) within the Asian HCC population and to investigate the impact of DRLRs on HCC. METHODS Utilising a combination of univariate Cox, Lasso-Cox, and multivariate Cox analyses, five pivotal DRLRs (AC099850.3, ZNF337-AS1, LINC01138, AL031985.3, AC131009.1) were identified, forming a robust prognostic signature. Subsequent validations included Receiver Operating Characteristic (ROC) and Concordance Index analyses, alongside Principal Component Analysis. Comprehensive bioinformatics analysis was performed on the hub DRLRs, followed by experimental validation using quantitative real-time polymerase chain reaction and cellular functional assays. RESULTS The risk score independently predicted prognosis, outperforming traditional clinical-pathological factors across varying ages, tumour stages, and pathological classifications in the cohort. A nomogram integrating these variables demonstrated capability in forecasting survival. Multivariate analysis confirmed that the risk score and AJCC TNM staging are independent prognostic factors for predicting overall survival (OS) in Asian HCC patients (both P < 0.001). The prognostic model's ROC area under the ROC values for 1-, 3-, and 5-year predictions were 0.837, 0.794, and 0.783, respectively, indicating its strong diagnostic and prognostic value. Pathway and immune landscape analyses elucidated the biological underpinnings and immune modulations associated with the high-risk group. Immune landscape analysis indicated that both immunescore (P < 0.001) and estimatescore (P < 0.05) were significantly decreased in the high-risk group, with both specific and non-specific immune responses being significantly suppressed, while the tumour immune dysfunction and exclusion score was notably increased (P < 0.001). Tumour mutational burden (TMB) analysis revealed a significantly higher TMB in the high-risk group (P = 0.033) and shorter OS for HCC patients in the high TMB subgroup (P = 0.002). Notably, Potential chemotherapeutic agents (PFI3, 5-Fluorouracil, BPD-00008900, GDC0810, and AZ6102) were identified for high-risk group. Experimental validations through quantitative PCR and in vitro assays confirmed the deregulation of these DRLRs in HCC, with functional studies highlighting the potential of ZNF337-AS1 silencing in curtailing tumour invasiveness. CONCLUSION Our investigations validate a DRLR-based risk scoring model as an effective prognostic tool for Asian HCC. This model not only enhances understanding of disulfidptosis's role in HCC but also facilitates personalised treatment strategies, potentially improving patient outcomes.
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Affiliation(s)
- Duo Shen
- Department of Gastroenterology, The Second People's Hospital of Changzhou, The Third Affiliated of Nanjing Medical University, Changzhou, Jiangsu, China
| | - Ling Sha
- Department of Neurology, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Ling Yang
- Department of Central Laboratory, Jurong Hospital Affiliated to Jiangsu University, 66 Ersheng Road, Jurong, Zhenjiang, 212400, Jiangsu, China
| | - Xuefeng Gu
- Department of Central Laboratory, Jurong Hospital Affiliated to Jiangsu University, 66 Ersheng Road, Jurong, Zhenjiang, 212400, Jiangsu, China.
- Department of Infectious Diseases, Jurong Hospital Affiliated to Jiangsu University, 66 Ersheng Road, Jurong, Zhenjiang, 212400, Jiangsu, China.
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Yang G, Ren Y, Li Y, Tang Y, Yuan F, Cao M, He Z, Su X, Shi Z, Hu Z, Deng M, Ren J, Yao Z. Post-treatment adverse events ranking in targeted immunotherapy for hepatocellular carcinoma: A network meta-analysis based on risk probability assessment. Crit Rev Oncol Hematol 2025; 211:104737. [PMID: 40252815 DOI: 10.1016/j.critrevonc.2025.104737] [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: 12/08/2024] [Revised: 04/14/2025] [Accepted: 04/17/2025] [Indexed: 04/21/2025] Open
Abstract
BACKGROUND Despite the rapid evolution of targeted and immunotherapies for hepatocellular carcinoma (HCC), a systematic comparison of their adverse event profiles remains limited. This review addresses this critical gap by synthesizing data from 13 randomized controlled trials (RCTs) to prioritize treatment regimens on the basis of safety, thereby guiding clinical decision-making in an era of expanding therapeutic options. METHODS Clinical studies focusing on targeted and immunotherapies in HCC patients were chosen from databases such as PubMed, Embase, Web of Science and the Cochrane Library, which spans from 2008 to 2023. Data processing and evaluation followed PRISMA guidelines, with a random-effects model employed to merge the data. Network models were then developed, with adverse events serving as the primary endpoint for analysis. RESULTS A comprehensive review of the relevant literature was conducted, identifying 13 randomized controlled trials (RCTs) encompassing 13 treatment protocols for HCC. This study included a total of 10,760 patients. Adverse events within the same category were initially consolidated, followed by the sequential construction of a network model to assess the risk probabilities associated with different targeted immunotherapy regimens for various adverse events and establish priority rankings. CONCLUSIONS Cabozantinib, camrelizumab, and their combination therapy for HCC are associated with a higher incidence of common adverse reactions, whereas durvalumab, lenvatinib, and their combination therapy are less likely to cause common adverse effects.
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Affiliation(s)
- Gaoyuan Yang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Yupeng Ren
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Yuxuan Li
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Yongchang Tang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Feng Yuan
- Department of General Surgery, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
| | - Mingbo Cao
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Zhiwei He
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Xiaorui Su
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Zheng Shi
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Ziyi Hu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Meihai Deng
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
| | - Jie Ren
- Department of Medical Ultrasonics, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Province Key Laboratory of Hepatology Research, Guangzhou 510630, China.
| | - Zhicheng Yao
- Department of Hepatobiliary and Pancreatic Surgery, Lingnan Hospital, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
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Zhang G, Zhang G, Zhao Y, Wan Y, Jiang B, Wang H. Unveiling the nexus of p53 and PD-L1: insights into immunotherapy resistance mechanisms in hepatocellular carcinoma. Am J Cancer Res 2025; 15:1410-1435. [PMID: 40371157 PMCID: PMC12070102 DOI: 10.62347/brto3272] [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: 03/25/2025] [Indexed: 05/16/2025] Open
Abstract
Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer worldwide, continues to pose a substantial health challenge with limited treatment options for advanced stages. Despite progress in therapies such as surgery, transplantation, and targeted treatments, prognosis remains bleak for many patients. The advent of immunotherapy has revolutionized the landscape of advanced HCC treatment, offering hope for improved outcomes. However, its efficacy is limited, with a modest response rate of approximately 20% as a single-agent therapy, underscoring the urgent need to decipher mechanisms of immunotherapy resistance. Tumor protein 53 gene (TP53), a pivotal tumor suppressor gene, and Programmed death ligand 1 (PD-L1), a crucial immune checkpoint ligand, play central roles in HCC's evasion of immune responses. Understanding how tumor protein 53 (p53) influences PD-L1 expression and immune system interactions is essential for unraveling the complexities of immunotherapy resistance mechanisms. Elucidating these molecular interactions not only enhances our understanding of HCC's underlying mechanisms but also lays the foundation for developing targeted treatments that may improve outcomes for patients with advanced-stage liver cancer. Ultimately, deciphering the nexus of p53 and PD-L1 in immunotherapy resistance promises to advance treatment strategies and outcomes in the challenging landscape of HCC. This review delves into the intricate relationship between p53 and PD-L1 concerning immunotherapy resistance in HCC, offering insights that could pave the way for novel therapeutic strategies aimed at enhancing treatment efficacy and overcoming resistance in advanced stages of the disease.
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Affiliation(s)
- Guoyuan Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, China
| | - Gan Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, China
| | - Yixuan Zhao
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, China
| | - Yunyan Wan
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, China
| | - Bin Jiang
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, China
| | - Huaxiang Wang
- Department of Hepatobiliary and Pancreatic Surgery, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei Province, China
- Department of Hepatobiliary and Pancreatic Surgery, Hubei Provincial Clinical Research Center for Precision Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of MedicineShiyan 442000, Hubei, 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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Huang J, Zou W, Lv Z, Han H, Huang J, Su H. Immune cell phenotypes as causal factors in liver disease progression revealed by Mendelian randomization. Sci Rep 2025; 15:12685. [PMID: 40221542 PMCID: PMC11993735 DOI: 10.1038/s41598-025-97429-x] [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: 06/17/2024] [Accepted: 04/04/2025] [Indexed: 04/14/2025] Open
Abstract
Immune cells are central mediators of the immune response and play critical roles in the pathogenesis and progression of liver diseases. Understanding the specific contributions of immune cells to liver disease progression is essential for developing targeted therapeutic strategies. In this study, we employed a two-sample Mendelian randomization (MR) approach to explore potential causal relationships between peripheral immune cell phenotypes and liver diseases, using genetic instrumental variables from large-scale genome-wide association studies (GWAS). Applying the inverse variance weighted (IVW) methods, we identified that monocyte count(odds ratio (OR) 0.81; 95% confidence interval (CI) 0.74-0.90; P = 5.95 × 10- 5, PFDR = 3.57 × 10- 4), CD3- lymphocyte/lymphocyte (OR 0.59, 95% CI 0.45-0.79; P = 3.29 × 10- 4, PFDR = 5.92 × 10- 3) and SSC-A (Side Scatter Area) on Natural Killer (NK) cells (OR 0.89, 95% CI 0.82-0.95; P = 1.37 × 10- 3, PFDR = 0.0396) acted as protective factors against alcoholic liver disease. Similarly, the trait HLA DR++ monocyte/monocyte was associated with a lower risk of autoimmune hepatitis (OR 0.56, 95% CI 0.41-0.79; P = 7.42 × 10- 4, PFDR = 0.0475). Conversely, an elevated blood monocytic Myeloid-Derived Suppressor Cells (MDSCs) count was associated with a higher risk of chronic hepatitis (OR 1.23, 95% CI 1.11-1.37; P = 1.13 × 10- 4, PFDR = 1.58 × 10- 3). Similarly, higher levels of HLA DR on CD14- CD16+ monocyte (OR 0.84, 95% CI 0.78-0.91; P = 2.07 × 10- 5, PFDR = 1.32 × 10- 3) conferred lower risk for cirrhosis of liver. In hepatic failure, CD39+ resting CD4 regulatory T cell count (OR 0.85, 95% CI 0.79-0.92; P = 1.70 × 10- 5, PFDR = 5.25 × 10- 3) played a protective role and CD28+ CD45RA- CD8dim T cell/CD8dim T cell (OR 1.14, 95% CI 1.06-1.22; P = 2.63 × 10- 4, PFDR = 0.0406) exhibited a risk function. Our findings highlight key immune pathways in liver disease progression and underscore potential immunomodulatory targets for future therapeutic interventions. Further research is warranted to clarify the mechanistic underpinnings of these associations.
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Affiliation(s)
- Jingtao Huang
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Wenlu Zou
- Department of Infectious Diseases, Qilu Hospital of Shandong University, Wenhua Xi Road 107, Jinan, 250012, Shandong, China
| | - Zhihua Lv
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Huan Han
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Jiapeng Huang
- Department of Thyroid Surgery, The First Hospital of China Medical University, No. 155 in Nanjing North Street, Heping Distinct, Shenyang, Liaoning, China.
| | - Hanwen Su
- Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
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Kim S, Byun HK, Sung W. Spatial Dose-Response Pattern Associated With Severe Radiation-Induced Lymphopenia in the Liver: A Voxel-Based Analysis. Int J Radiat Oncol Biol Phys 2025:S0360-3016(25)00357-8. [PMID: 40220962 DOI: 10.1016/j.ijrobp.2025.03.082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 02/06/2025] [Accepted: 03/30/2025] [Indexed: 04/14/2025]
Abstract
PURPOSE This study aimed to investigate the dose-response pattern of severe radiation-induced lymphopenia (SRIL) in patients with hepatocellular carcinoma (HCC) undergoing radiation therapy (RT). We focused on identifying specific liver regions associated with SRIL development. METHODS AND MATERIALS We analyzed data from 75 patients with HCC treated with RT. Segment-wise and voxel-based analyses (VBAs) were conducted to investigate the spatial relationship between delivered dose and SRIL occurrence (absolute lymphocyte count [ALC] < 500/µL). Logistic regression was performed for segment-wise analysis, whereas generalized linear models and Mann-Whitney U tests were employed for VBAs. The liver was divided into Couinaud segments, and dose distributions were analyzed at both the segment and voxel levels. RESULTS Segment-wise logistic regression revealed that pre-RT ALC (odds ratio [OR], 0.006; P = .002), liver segments 1 (OR, 1.228; P = .048), and 7 (OR, 1.314; P = .016) were statistically associated with SRIL occurrence. VBAs demonstrated heterogeneous dose-response patterns across the liver, with segment 1 consistently showing the strongest association with SRIL across different statistical methods. Segment 1 contained the highest proportion of statistically significant voxels (94%) in relation to SRIL occurrence among all liver segments. CONCLUSIONS This study revealed an inhomogeneous dose-response pattern regarding SRIL manifestation in the liver. Our results suggest that certain regions within a single organ may require rigorous dosimetric constraints to mitigate SRIL.
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Affiliation(s)
- Seohan Kim
- Department of Biomedical Engineering, College of Medicine, the Catholic University of Korea, Seoul, South Korea; Department of Medical Sciences, Graduate School of the Catholic University of Korea, Seoul, South Korea; CMC Institute for Basic Medical Science, the Catholic Medical Center of the Catholic University of Korea, Seoul, South Korea
| | - Hwa Kyung Byun
- Department of Radiation Oncology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, South Korea.
| | - Wonmo Sung
- Department of Biomedical Engineering, College of Medicine, the Catholic University of Korea, Seoul, South Korea; Department of Medical Sciences, Graduate School of the Catholic University of Korea, Seoul, South Korea; CMC Institute for Basic Medical Science, the Catholic Medical Center of the Catholic University of Korea, Seoul, South Korea.
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Gao X, Xu Y, Hu X, Chen J, Zhang D, Xu X. Comprehensive analysis of mitochondrial solute carrier family 25 (SLC25) identifies member 19 (SLC25A19) as a regulatory factor in hepatocellular carcinoma. Gene 2025; 944:149299. [PMID: 39892835 DOI: 10.1016/j.gene.2025.149299] [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: 11/01/2024] [Revised: 01/08/2025] [Accepted: 01/28/2025] [Indexed: 02/04/2025]
Abstract
BACKGROUND The mitochondrial solute carrier family 25 (SLC25) is known to play a pivotal role in oncogenesis, yet its specific involvement in hepatocellular carcinoma (HCC) remains poorly elucidated. METHODS In this study, we performed a clustering analysis of HCC patients in the Cancer Genome Atlas database based on the expression levels of SLC25 members, and conducted clinical feature analysis for each patient within the clusters. Subsequently, we developed a prognostic model using a Lasso regression approach with SLC25A19, SLC25A49, and SLC25A51 as features, and generated a risk score for each HCC patient. We then identified SLC25A19 as a potential prognostic marker for HCC through single-cell analysis, and validated this finding using in vitro and in vivo experiments. RESULTS Our results revealed significant differences in the expression of most SLC25 family members in HCC patients, enabling the stratification of patients into three clusters, with those in cluster 1 exhibiting the most favorable prognosis and showing a correlation with enhanced immune infiltration. The risk scores derived from the features SLC25A19, SLC25A49, and SLC25A51 effectively predicted the prognosis of HCC patients, with area under the curve (AUC) values exceeding 0.7 in the test group. Single-cell analysis further demonstrated h eightened expression of SLC25A19 in the immune microenvironment of HCC, and in vitro experiments indicated that SLC25A19 may regulate the proliferation, migration, invasion, cycle, and apoptosis of liver cancer cells through the Wnt pathway. In the HepG2 animal model, overexpression of SLC25A19 significantly promotes tumor growth, while knockdown inhibits tumor growth. Analysis of patient tumor tissues shows that SLC25A19 is highly expressed in liver cancer tissues and is associated with CD8+ T cell infiltration. CONCLUSIONS In conclusion, our comprehensive analysis of the role of SLC25 in HCC unveiled SLC25A19 as a potential regulatory factor in HCC.
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Affiliation(s)
- Xueke Gao
- Renmin Hospital of Wuhan University, Wuhan, Hubei, China 430060
| | - Yangtao Xu
- Renmin Hospital of Wuhan University, Wuhan, Hubei, China 430060
| | - Xinyao Hu
- Renmin Hospital of Wuhan University, Wuhan, Hubei, China 430060
| | - Jiayu Chen
- Renmin Hospital of Wuhan University, Wuhan, Hubei, China 430060
| | - Daoming Zhang
- Renmin Hospital of Wuhan University, Wuhan, Hubei, China 430060
| | - Ximing Xu
- Renmin Hospital of Wuhan University, Wuhan, Hubei, China 430060.
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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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Dzama-Karels M, Kuhlers P, Sokolowski M, Brinkman JA, Morris JP, Raab JR. Menin-MLL1 complex cooperates with NF-Y to promote HCC survival. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.05.647381. [PMID: 40291722 PMCID: PMC12026816 DOI: 10.1101/2025.04.05.647381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Identification of new therapeutic targets in hepatocellular carcinoma (HCC) remains critical. Chromatin regulating complexes are frequently mutated or aberrantly expressed in HCC, suggesting dysregulation of chromatin environments is a key feature driving liver cancer. To investigate whether the altered chromatin state in HCC cells could be targeted, we designed and utilized an epigenome-focused CRISPR library that targets genes involved in chromatin regulation. This focused approach allowed us to test multiple HCC cell lines in both 2D and 3D growth conditions, which revealed striking differences in the essentiality of genes involved in ubiquitination and multiple chromatin regulators vital for HCC cell survival in 2D but whose loss promoted growth in 3D. We found the core subunits of the menin-MLL1 complex among the strongest essential genes for HCC survival in all screens and thoroughly characterized the mechanism through which the menin-MLL1 complex promotes HCC cell growth. Inhibition of the menin-MLL1 interaction led to global changes in occupancy of the complex with concomitant decreases in H3K4me3 and expression of genes involved in PI3K/AKT/mTOR signaling pathway. Menin inhibition affected chromatin accessibility in HCC cells, revealing that increased chromatin accessibility at sites not bound by menin-MLL1 was associated with the recruitment of the pioneer transcription factor complex NF-Y. A CRISPR/Cas9 screen of chromatin regulators in the presence of menin inhibitor SNDX-5613 revealed a significantly increased cell death when combined with NFYB knockout. Together these data show that menin-MLL1 is necessary for HCC cell survival and cooperates with NF-Y to regulate oncogenic gene transcription.
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Shu Q, Wang Q, Yang X, Li B. ARIH2 serves as a potential prognostic biomarker for hepatocellular carcinoma associated with immune infiltration and ferroptosis. Front Immunol 2025; 16:1548691. [PMID: 40260250 PMCID: PMC12009847 DOI: 10.3389/fimmu.2025.1548691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/17/2025] [Indexed: 04/23/2025] Open
Abstract
Background Ariadne homolog 2 (ARIH2) has been demonstrated to be upregulated in various human cancer tissues. Nevertheless, the underlying biological function of ARIH2 in the progression of hepatocellular carcinoma (HCC) remains ambiguous. Hence, we conducted a comprehensive bioinformatics analysis on the liver hepatocellular carcinoma (LIHC) dataset to explore the role of ARIH2 in tumorigenesis. Methods The mRNA and protein expression of ARIH2 was analyzed by using data from public databases and verified through immunohistochemical staining and Western blot. Logistic regression, Cox regression, receiver operating characteristic curve (ROC), Kaplan-Meier analysis and nomogram model were employed to assess the association between ARIH2 and the clinicopathological characteristics of HCC. We utilized functional enrichment analysis to investigate the potential pathways of ARIH2 in the progression of HCC. The association of ARIH2 with immune infiltration, ferroptosis and immune checkpoint genes was further evaluated. Finally, the correlation between ARIH2 and the IC50 of chemotherapeutic drugs was analyzed in HCC. Results Our study discovered that ARIH2 was up-regulated in HCC tumor tissues compared with the control group. ARIH2 expression could effectively distinguish tumor tissues from normal liver tissues. The genes related to ARIH2 showed differential expression in pathways involving immune system-related pathways and ion channels. We identified a significant association between the expression level of ARIH2 in HCC tissues and immune infiltration, immune checkpoint genes and ferroptosis. The expression level of ARIH2 was significantly correlated with the clinical stage, histological pathological grade and clinical characteristics of HCC, and could independently predict overall survival. Conclusions The expression level of ARIH2 may serve as a promising biomarker for the diagnosis and prognosis of HCC, as well as a potential drug target, which holds great significance for the development of targeted therapy for HCC.
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Affiliation(s)
| | | | - Xiaoli Yang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Bo Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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Zhang C, Wang H, Li X, Jiang Y, Sun G, Yu H. Enhancing antitumor immunity: the role of immune checkpoint inhibitors, anti-angiogenic therapy, and macrophage reprogramming. Front Oncol 2025; 15:1526407. [PMID: 40260303 PMCID: PMC12009726 DOI: 10.3389/fonc.2025.1526407] [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: 11/11/2024] [Accepted: 03/19/2025] [Indexed: 04/23/2025] Open
Abstract
Cancer treatment has long been hindered by the complexity of the tumor microenvironment (TME) and the mechanisms that tumors employ to evade immune detection. Recently, the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic therapies has emerged as a promising approach to improve cancer treatment outcomes. This review delves into the role of immunostimulatory molecules and ICIs in enhancing anti-tumor immunity, while also discussing the therapeutic potential of anti-angiogenic strategies in cancer. In particular, we highlight the critical role of endoplasmic reticulum (ER) stress in angiogenesis. Moreover, we explore the potential of macrophage reprogramming to bolster anti-tumor immunity, with a focus on restoring macrophage phagocytic function, modulating hypoxic tumor environments, and targeting cytokines and chemokines that shape immune responses. By examining the underlying mechanisms of combining ICIs with anti-angiogenic therapies, we also review recent clinical trials and discuss the potential of biomarkers to guide and predict treatment efficacy.
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Affiliation(s)
- Chong Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Xinying Li
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yuxin Jiang
- Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guoping Sun
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hanqing Yu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Li Y, Bai L, Liang H, Yan P, Chen H, Cao Z, Shen Y, Wang Z, Huang M, He B, Hao Q, Mei Y, Wei H, Ding C, Jin J, Wang Y. A BPTF-specific PROTAC degrader enhances NK cell-based cancer immunotherapy. Mol Ther 2025; 33:1566-1583. [PMID: 39935175 PMCID: PMC11997503 DOI: 10.1016/j.ymthe.2025.02.013] [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: 05/29/2024] [Revised: 12/19/2024] [Accepted: 02/06/2025] [Indexed: 02/13/2025] Open
Abstract
Natural killer (NK) cell-based immunotherapy shows promise in cancer treatment, but its efficacy remains limited, necessitating the development of novel strategies. In this study, we demonstrate that the epigenetic factor bromodomain PHD-finger containing transcription factor (BPTF) hinders hepatocellular carcinoma (HCC) recognition by NK cells through its PHD finger's interpretation of H3K4me3. We have generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degrades human and murine BPTF. The degradation of BPTF using PROTACs directly enhances the abundance of natural cytotoxicity receptor ligands on HCC cells, facilitating their recognition by NK cells and thereby augmenting NK cell cytotoxicity against HCC both in vitro and in vivo. Through multidisciplinary techniques, our findings establish targeting BPTF with PROTACs as a promising approach to overcome immune evasion of HCC from NK cells and provide a new strategy to enhance NK cell-based cancer immunotherapy.
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Affiliation(s)
- Yunjia Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Lin Bai
- State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Human Phenome Institute, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200433, China
| | - Hao Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Peidong Yan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Hao Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Zhuoxian Cao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Yiqing Shen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Zhongyv Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Mei Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Bin He
- State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Quan Hao
- School of Biomedical Sciences, University of Hong Kong, Hong Kong, China
| | - Yide Mei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Haiming Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
| | - Chen Ding
- State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Human Phenome Institute, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200433, China.
| | - Jing Jin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
| | - Yi Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
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Ding G, Li K. A CT-Based Clinical-Radiomics Nomogram for Predicting the Overall Survival to TACE Combined with Camrelizumab and Apatinib in Patients with Advanced Hepatocellular Carcinoma. Acad Radiol 2025; 32:1993-2004. [PMID: 39578199 DOI: 10.1016/j.acra.2024.10.052] [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: 09/23/2024] [Revised: 10/16/2024] [Accepted: 10/30/2024] [Indexed: 11/24/2024]
Abstract
RATIONALE AND OBJECTIVES To construct a computed tomography (CT)-based clinical-radiomics nomogram for estimating overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients receiving transcatheter arterial chemoembolization (TACE) in combination with camrelizumab and apatinib. METHODS A retrospective recruitment of 150 patients with clinically or pathologically confirmed HCC was conducted, followed by their division into training cohort (n = 105) and test cohort (n = 45). To generate the radiomics score (Rad-score), a series of analyses were performed, including Pearson correlation analysis, univariate Cox analysis, and least absolute shrinkage and selection operator Cox regression analysis. Subsequently, a clinical-radiomics nomogram was constructed using the Rad-score combined with independent clinical prognostic factors, followed by assessments of its calibration, discrimination, reclassification, and clinical utility. RESULTS Five CT radiomics features were selected. The Rad-score showed a significant correlation with OS (P < 0.001). The clinical-radiomics nomogram demonstrated superior performance in estimating OS, with a concordance index (C-index) of 0.840, compared to the radiomics nomogram (C-index: 0.817) and the clinical nomogram (C-index: 0.661). It also exhibited high 1-year and 2-year area under the curves of 0.936 and 0.946, respectively. Additionally, the clinical-radiomics nomogram markedly enhanced classification accuracy for OS outcomes, as evidenced by net reclassification improvement and integrated discrimination improvement. Decision curve analysis confirmed its clinical utility. CONCLUSION A CT-based clinical-radiomics nomogram exhibits strong potential for predicting OS in advanced HCC patients undergoing TACE combined with camrelizumab and apatinib.
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Affiliation(s)
- Guangyao Ding
- Department of General Surgery, Hefei BOE Hospital, Hefei, Anhui, China
| | - Kailang Li
- Department of General Surgery, Hefei BOE Hospital, Hefei, Anhui, China.
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Wang Y, Wang H, Liu Z, Chang Z. Evolution of transarterial chemoembolization-related liver abscess over time: a systematic review and meta-analysis. Quant Imaging Med Surg 2025; 15:2707-2721. [PMID: 40235776 PMCID: PMC11994569 DOI: 10.21037/qims-24-1166] [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: 06/10/2024] [Accepted: 02/21/2025] [Indexed: 04/17/2025]
Abstract
Background Transarterial chemoembolization (TACE) is a primary method for treating malignant liver tumors; however, the occurrence of liver abscesses after TACE has always been a concern. With the evolution of time, TACE techniques and practical experience continue to advance, leading to a deeper understanding of post-TACE liver abscesses. This meta-analysis aimed to comprehensively examine the occurrence of liver abscesses after TACE and focus on its changing trends. Methods Two researchers reviewed the databases of PubMed, Embase, and Web of Science to identify articles that reported liver abscess formation after TACE in patients with hepatic malignant tumor. The search was conducted from the date of establishment of each database up to January 2023. After screening the articles and extracting the data, we used Review Manager 5.3 and Stata 16.0 for analysis and processing. Results This meta-analysis included a total of 32 studies, comprising 254,408 TACE patients, of whom 642 developed liver abscesses after TACE. The pooled incidence rate of liver abscess formation after TACE was 0.54%. The heterogeneity was considerable and significant. Subgroup analysis revealed a significant impact of the evolution of time on the incidence of liver abscess formation after TACE. The incidence was shown to have decreased from 0.61% in the initial 5 years to 0.47% in the most recent 5 years, with statistical significance. Liver metastasis and type 2 biliary abnormality were significantly associated with the development of liver abscess. Mortality directly associated with liver abscess was 7.73% and was gradually decreasing, from over 50% in the 1990s to 5.48% in the past decade, with a statistically significant difference. Conclusions The formation of liver abscess was a relatively low-incidence complication following TACE for malignant liver tumors, with clearly defined risk factors. Moreover, both the incidence and mortality rates of liver abscess were gradually decreasing. These findings provide valuable insights for future clinical practice.
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Affiliation(s)
- Yunan Wang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hairui Wang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhaoyu Liu
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhihui Chang
- Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China
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Martínez-Jiménez F, Chowell D. Genetic immune escape in cancer: timing and implications for treatment. Trends Cancer 2025; 11:286-294. [PMID: 39632211 PMCID: PMC11981860 DOI: 10.1016/j.trecan.2024.11.002] [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: 10/06/2024] [Revised: 11/04/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024]
Abstract
Genetic immune escape (GIE) alterations pose a significant challenge in cancer by enabling tumors to evade immune detection. These alterations, which can vary significantly across cancer types, may often arise early in clonal evolution and contribute to malignant transformation. As tumors evolve, GIE alterations are positively selected, allowing immune-resistant clones to proliferate. In addition to genetic changes, the tumor microenvironment (TME) and non-genetic factors such as inflammation, smoking, and environmental exposures play crucial roles in promoting immune evasion. Understanding the timing and mechanisms of GIE, alongside microenvironmental influences, is crucial for improving early detection and developing more effective therapeutic interventions. This review highlights the implications of GIE in cancer development and immunotherapy resistance, and emphasizes the need for integrative approaches.
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Affiliation(s)
- Francisco Martínez-Jiménez
- Systems Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Hartwig Medical Foundation, Amsterdam, The Netherlands.
| | - Diego Chowell
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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Kang W, Tang P, Luo Y, Lian Q, Zhou X, Ren J, Cong T, Miao L, Li H, Huang X, Ou A, Li H, Yan Z, Di Y, Li X, Ye F, Zhu X, Yang Z. Multiparametric MRI-based Machine Learning Radiomics for Predicting Treatment Response to Transarterial Chemoembolization Combined with Targeted and Immunotherapy in Unresectable Hepatocellular Carcinoma: A Multicenter Study. Acad Radiol 2025; 32:2013-2026. [PMID: 39609145 DOI: 10.1016/j.acra.2024.10.038] [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: 09/12/2024] [Revised: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 11/30/2024]
Abstract
RATIONALE AND OBJECTIVES To develop and validate multiple machine learning predictive models incorporating clinical features and pretreatment multiparametric magnetic resonance imaging (MRI) radiomic features for predicting treatment response to transarterial chemoembolization combined with molecular targeted therapy plus immunotherapy in unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS This retrospective study involved 276 patients with unresectable HCC who received combination therapy from 4 medical centers. Patients were divided into one training cohort and two independent external validation cohorts. 16 radiomic features from six multiparametric MRI sequences and 2 clinical features were used to build six machine learning models. The models were evaluated using the area under the curve (AUC), decision curve analysis, and incremental predictive value. RESULTS Alpha-fetoprotein and neutrophil-to-lymphocyte ratio are clinical independent predictors of treatment response. In the training cohort and two external validation cohorts, the AUCs and 95% confidence intervals for predicting treatment response were respectively 0.782 (0.698-0.857) 0.695 (0.566-0.823), and 0.679 (0.542-0.810) for the clinical model; 0.942 (0.903-0.974), 0.869 (0.761-0.949), and 0.868 (0.769-0.942) for the radiomics model; and 0.956 (0.920-0.984), 0.895 (0.810-0.967), and 0.892 (0.804-0.957) for the combined clinical-radiomics model. In the three cohorts, the incremental predictive value of the radiomics model over the clinical model was 49.2% (P < 0.001), 28.8% (P < 0.001), and 31.5% (P < 0.001). CONCLUSION The combined clinical-radiomics model may provide a reliable and non-invasive tool to predict individual treatment responses and guide and improve clinical decision-making in combination therapy of HCC patients.
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Affiliation(s)
- Wendi Kang
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Peiyun Tang
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun 130000, China
| | - Yingen Luo
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Qicai Lian
- Department of Interventional Radiology, the Affiliated Cancer Hospital of Guizhou Medical University, Guiyang 550000, China
| | - Xuan Zhou
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, 410013 Hunan, China
| | - Jinrui Ren
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Tianhao Cong
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lei Miao
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hang Li
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiaoyu Huang
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Aixin Ou
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hao Li
- Department of Interventional Radiology, The First Hospital of China Medical University, No.155 Nanjing Road, Heping District, Shenyang 110001, Liaoning, China
| | - Zhentao Yan
- Department of Interventional Radiology, The First Hospital of China Medical University, No.155 Nanjing Road, Heping District, Shenyang 110001, Liaoning, China
| | - Yingjie Di
- Department of Interventional Therapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, China
| | - Xiao Li
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Feng Ye
- Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiaoli Zhu
- Department of Interventional Radiology, The First Affiliated Hospital, Soochow University, No.188 Shizi Road, Suzhou 215006, China
| | - Zhengqiang Yang
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
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Zheng B, Wang H, Zhai S, Li J, Lu K. Mitochondria-targeted photothermal-chemodynamic therapy enhances checkpoint blockade immunotherapy on colon cancer. Mater Today Bio 2025; 31:101542. [PMID: 40018055 PMCID: PMC11867542 DOI: 10.1016/j.mtbio.2025.101542] [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: 12/02/2024] [Revised: 01/28/2025] [Accepted: 02/01/2025] [Indexed: 03/01/2025] Open
Abstract
Immunotherapy has emerged as a hotspot for cancer treatment. However, the response rate of monotherapy remains relatively low in clinical settings. Photothermal therapy (PTT), which employs light energy to ablate tumors, can also activate tumor-specific immune responses. This effect has been attributed in several studies to the release of damage-associated molecular patterns (DAMPs) triggered by mitochondrial injury. We propose that mitochondria-targeted PTT may better synergize with immunotherapy. Herein, we constructed a multifunctional nanoplatform that enables mitochondria-targeted photothermal-chemodynamic combination therapy by conjugating indocyanine green-thiol (ICG-SH) and mercaptoethyl-triphenylphosphonium (TPP-SH) onto polyvinyl pyrrolidone (PVP)-coated gold-copper nanoparticles (AIT). Upon near-infrared light (NIR) irradiation, AIT ablates cancer cells and amplifies the effect of chemodynamic therapy (CDT), thereby inducing apoptosis in the tumor. The combination of CDT and PTT promotes immunogenic cell death, which could synergize with checkpoint blockade immunotherapy. In a bilateral mouse colon cancer model, we observed complete eradication of light-irradiated primary tumors and significant inhibition of distant untreated tumors in the group treated with AIT plus anti-PD-1 (αPD-1). We found a significant increase in serum levels of pro-inflammatory factors, including interleukin-6 (IL-6), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), following PTT/CDT/immunotherapy treatment, suggesting effective activation of the immune response. The enhanced immunogenicity caused by AIT with αPD-1 treatment resulted in efficient antigen presentation, as indicated by the increased infiltration of dendritic cells (DCs) into the tumor-draining lymph nodes (LNs). We also observed enhanced infiltration of CD8+ T cells in distant tumors in the AIT with αPD-1 group compared to αPD-1 alone. Hence, mitochondria-targeting represents an effective strategy to potentiate the combination of photothermal, chemodynamic, and immune checkpoint blockade therapies for the treatment of metastatic cancer.
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Affiliation(s)
- Benchao Zheng
- Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, PR China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, PR China
| | - Hongbo Wang
- Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, PR China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, PR China
| | - Shiyi Zhai
- Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, PR China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, PR China
| | - Jiangsheng Li
- Key Laboratory of Carcinogenesis and Translational Research of Ministry of Education, Key Laboratory for Research and Evaluation of Radiopharmaceuticals of National Medical Products Administration, Department of Nuclear Medicine, Peking University Cancer Hospital, Beijing, 100142, PR China
| | - Kuangda Lu
- Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, PR China
- Institute of Advanced Clinical Medicine, Peking University, Beijing, 100191, PR China
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Lv J, Gan FY, Li MH, Yin QJ. Silencing NCAPD3 Inhibits Tumor Growth and Metastasis in Hepatocellular Carcinoma by Suppressing PI3K-AKT Signalling Pathway. Curr Med Sci 2025; 45:253-263. [PMID: 40029498 DOI: 10.1007/s11596-025-00026-2] [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] [Received: 11/29/2024] [Revised: 01/23/2025] [Accepted: 01/26/2025] [Indexed: 03/05/2025]
Abstract
OBJECTIVE To evaluate the expression pattern of non-SMC condensin II complex subunit D3 (NCAPD3) in hepatocellular carcinoma (HCC) tissues, assess its association with clinical characteristics, and explore the effects of NCAPD3 on HCC cells and the potential underlying mechanisms. METHODS NCAPD3 expression in HCC tumors and adjacent noncancerous tissues was quantified via quantitative PCR. Patients were divided into high- and low-expression groups on the basis of NCAPD3 levels, and associations with clinical parameters were assessed. The effects of NCAPD3 knockdown and the phosphatidylinositol-3-kinase (PI3K) agonist Y-P 740 on cell functions were examined via cell proliferation, Transwell migration, and invasion assays. Differentially expressed genes following NCAPD3 knockdown in SMMC-7721 cells were identified via mRNA sequencing. Western blotting was performed to measure NCAPD3, AKT serine/threonine kinase 1 (AKT1), and phosphorylated AKT1 levels. RESULTS NCAPD3 mRNA expression was notably upregulated in HCC tissues as compared with that in adjacent noncancer tissues. A positive correlation was observed between NCAPD3 expression and both lymphatic and distant metastases in patients with HCC. NCAPD3 knockdown reduced the proliferation and metastasis of SMMC-7721 and Huh-7 cells. mRNA sequencing revealed 140 downregulated genes and 125 upregulated genes. Further validation experiments confirmed that NCAPD3 modulated the PI3K-AKT signalling pathway and that the PI3K agonist Y-P 740 counteracted the effects of NCAPD3 knockdown. CONCLUSIONS Elevated NCAPD3 expression was strongly correlated with HCC metastasis. NCAPD3 inhibition impedes HCC cell growth and metastatic potential by suppressing the PI3K-AKT signalling pathway.
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Affiliation(s)
- Jun Lv
- Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
| | - Fu-Yuan Gan
- Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Ming-Hao Li
- Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Qing-Jun Yin
- Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
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Vaghjiani R, Wu R, Tung KH, Ishikawa T, Takabe K. Angiogenesis Is Associated With Aggressive Biology That Counterbalances With Tumor Immunogenicity in Hepatocellular Carcinoma. World J Oncol 2025; 16:173-181. [PMID: 40162113 PMCID: PMC11954604 DOI: 10.14740/wjon2009] [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: 12/09/2024] [Accepted: 01/17/2025] [Indexed: 04/02/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) is an arterialized tumor; thus, anti-angiogenesis targeted therapy is in clinical practice. Herein, we hypothesized that HCC with high angiogenesis is biologically aggressive with worse survival. Methods Angiogenesis score (AS) was derived from the Molecular Signatures Database (MSigDB) Hallmark Angiogenesis Gene Set, and median was used to divide high versus low groups. Transcriptome of HCC patients of The Cancer Genome Atlas (TCGA, n = 386) and GSE76427 (n = 115) cohorts were analyzed. Results High AS correlated with angiogenesis-related gene expressions. Both microvascular and lymphatic endothelial cell infiltrations were higher in high angiogenesis HCC. Surprisingly, no survival difference was seen with varying levels of angiogenesis. High angiogenesis significantly enriched tumor aggravating signaling pathways: glycolysis, Notch, Hedgehog, KRAS, epithelial mesenchymal transition, and transforming growth factor-beta (TGF-β) in Gene Set Enrichment Analysis (GSEA), but also infiltrated less CD8+ T cells and T-helper 1 cells, and higher M1 macrophages and conventional dendritic cells (cDCs) with elevated cytolytic activity score in both cohorts. In agreement, immune response-related gene sets: inflammatory response, tumor necrosis factor-alpha (TNF-α) signaling, allograft rejection, interferon-alpha, and interferon-gamma were all enriched to high angiogenesis HCC. Programmed cell death protein 1 (PD1), programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) were higher in high angiogenesis HCC in TCGA, but not in GSE76427 cohort. Conclusions Angiogenesis quantified using transcriptome of HCC patients demonstrated that it is associated with aggressive biology but also with tumor immunogenicity and immune response that counterbalance and did not reflect in survival. Given high expression of immune checkpoint molecules, we cannot help but speculate that immunotherapy may be useful for high angiogenesis HCC patients.
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Affiliation(s)
- Raj Vaghjiani
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- These authors contributed equally to this work
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
- These authors contributed equally to this work
| | - Kaity H. Tung
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima, Japan
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
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Chen L, Tang W, Liu J, Zhu M, Mu W, Tang X, Liu T, Zhu Z, Weng L, Cheng Y, Zhang Y, Chen X. On-demand reprogramming of immunosuppressive microenvironment in tumor tissue via multi-regulation of carcinogenic microRNAs and RNAs dependent photothermal-immunotherapy using engineered gold nanoparticles for malignant tumor treatment. Biomaterials 2025; 315:122956. [PMID: 39549441 DOI: 10.1016/j.biomaterials.2024.122956] [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: 07/20/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/18/2024]
Abstract
The frequent immune escape of tumor cells and fluctuating therapeutic efficiency vary with each individual are two critical issues for immunotherapy against malignant tumor. Herein, we fabricated an intelligent core-shell nanoparticle (SNAs@CCMR) to significantly inhibit the PD-1/PD-L1 mediated immune escape by on-demand regulation of various oncogenic microRNAs and perform RNAs dependent photothermal-immunotherapy to achieve precise and efficient treatment meeting the individual requirements of specific patients by in situ generation of customized tumor-associated antigens. The SNAs@CCMR consisted of antisense oligonucleotides grafted gold nanoparticles (SNAs) as core and TLR7 agonist imiquimod (R837) functionalized cancer cell membrane (CCM) as shell, in which the acid-labile Schiff base bond was used to connect the R837 and CCM. During therapy, the acid environment of tumor tissue cleaved the Schiff base to generate free R837 and SNAs@CCM. The SNAs@CCM further entered tumor cells via CCM mediated internalization, and then specifically hybridized with over-expressed miR-130a and miR-21, resulting in effective inhibition of the migration and PD-L1 expression of tumor cells to avoid their immune escape. Meanwhile, the RNAs capture also caused significant aggregation of SNAs, which immediately generated photothermal agents within tumor cells to perform highly selective photothermal therapy under NIR irradiation. These chain processes not only damaged the primary tumor, but also produced plenty of tumor-associated antigens, which matured the surrounding dendritic cells (DCs) and activated anti-tumor T cells along with the released R837, resulting in the enhanced immunotherapy with suppressive immune escape. Both in vivo and in vitro experiments demonstrated that our nanoparticles were able to inhibit primary tumor and its metastasis via multi-regulation of carcinogenic microRNAs and RNAs dependent photothermal-immune activations, which provided a promising strategy to reprogram the immunosuppressive microenvironment in tumor tissue for better malignant tumor therapy.
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Affiliation(s)
- Li Chen
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Wenjun Tang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jie Liu
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Man Zhu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Wenyun Mu
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Xiaoyu Tang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Tao Liu
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Zeren Zhu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Lin Weng
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Yumeng Cheng
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yanmin Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Xin Chen
- Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
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Yang J, Choi WM, Kim HD, Choi J, Yoo C, Lee D, Shim JH, Kim KM, Lim YS, Lee HC. Higher Risk of Proteinuria with Atezolizumab plus Bevacizumab than Lenvatinib in First-Line Systemic Treatment for Hepatocellular Carcinoma. Liver Cancer 2025; 14:180-192. [PMID: 40255873 PMCID: PMC12005701 DOI: 10.1159/000541621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 09/22/2024] [Indexed: 01/03/2025] Open
Abstract
Introduction Proteinuria presents a challenging complication during systemic therapy for hepatocellular carcinoma (HCC). This study aims to identify risk factors for proteinuria in patients with HCC treated with atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic treatment. Methods A retrospective analysis was conducted on 622 consecutive patients with unresectable HCC who received Atezo/Bev or LEN as first-line systemic treatment between October 2013 and October 2022. Cumulative incidence of proteinuria was estimated using Kaplan-Meier curves and compared using log-rank tests. Risk factors for proteinuria were identified using Cox proportional-hazard models, along with propensity score-matched and subgroup analyses. Results Among 367 patients treated with Atezo/Bev and 255 with LEN, the cumulative incidence of proteinuria at 12 months was 27.5%. In the multivariable analysis, Atezo/Bev treatment (adjusted HR [aHR]: 1.57; 95% CI: 1.03-2.42), diabetes (aHR: 1.64; 95% CI: 1.03-2.61), hypertension (aHR: 2.27; 95% CI: 1.04-4.97), Child-Pugh class B (aHR: 3.43; 95% CI: 1.34-8.78), macrovascular invasion (MVI; aHR: 1.58; 95% CI: 1.04-2.38), and an estimated glomerular filtration rate ≤60 mL/min/1.73 m2 (aHR: 3.21; 95% CI: 1.84-5.62) were identified as risk factors for proteinuria. A higher risk of proteinuria in Atezo/Bev patients compared with LEN was consistently observed in the PS-matched cohort, particularly pronounced in subgroups with MVI (HR: 2.84; 95% CI: 1.23-6.54) compared with those without MVI (HR: 1.31; 95% CI: 0.69-2.47). Conclusions Patients treated with Atezo/Bev as first-line systemic treatment for HCC exhibited a higher risk of proteinuria compared with those with LEN, particularly when accompanied by MVI.
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Affiliation(s)
- Jiwon Yang
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Danbi Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Gu Y, Zhang Z, Huang H, Zhu W, Liu H, Zhang R, Weng N, Sun X. The dual role of CXCL9/SPP1 polarized tumor-associated macrophages in modulating anti-tumor immunity in hepatocellular carcinoma. Front Immunol 2025; 16:1528103. [PMID: 40230843 PMCID: PMC11994707 DOI: 10.3389/fimmu.2025.1528103] [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: 11/14/2024] [Accepted: 03/13/2025] [Indexed: 04/16/2025] Open
Abstract
Introduction The main challenge for cancer therapy lies in immuno-suppressive tumor micro-environment. Reprogramming tumor-associated macrophages (TAMs) into an anti-tumor phenotype is a promising strategy. Methods A comprehensive analysis by combing multi-regional single-cell, bulk and spatial transcriptome profiling with radiomics characterization was conducted to dissect the heterogeneity of TAMs and resolve the landscape of the CXCL9:SPP1 (CS) macrophage polarity in HCC. Results TAMs were particularly increased in HCC. SPP1+ TAMs and CXCL9+ TAMs were identified as the dominant subtypes with different evolutionary trajectories. SPP1+ TAMs, located in the tumor core, co-localized with cancer-associated fibroblasts to promote tumor growth and further contributed to worse prognosis. In contrast, CXCL9+ TAMs, located in the peritumoral region, synergized with CD8+ T cells to create an immunostimulatory micro-environment. For the first time, we explored the applicability of CS polarity in HCC tumors and revealed several key transcription factors involved in shaping this polarity. Moreover, CS polarity could serve as a potential indicator of prognostic and micro-environmental status for HCC patients. Based on medical imaging data, we developed a radiomics tool, RCSP (Radiogenomics-based CXCL9/SPP1 Polarity), to assist in non-invasively predicting the CS polarity in HCC patients. Conclusion Our research sheds light on the regulatory roles of SPP1+ TAMs and CXCL9+ TAMs in the micro-environment and provides new therapeutic targets or insights for the reprogramming of targeted macrophages in HCC.
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Affiliation(s)
- Yu Gu
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Zhihui Zhang
- College of Acupuncture-Moxibustion and Tuina, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hao Huang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Wenyong Zhu
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Hongjia Liu
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Rongxin Zhang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Nan Weng
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Xiao Sun
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
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