Hepatic arterial infusion chemotherapy (HAIC) with a combination of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown excellent local control for patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC). In China, both camrelizumab (a programmed cell death-1 [PD-1] inhibitor) and sorafenib have been approved for the first-line treatment of advanced HCC. This study aimed to investigate the efficacy and safety of hepatic artery infusion of FOLFOX chemotherapy plus camrelizumab combined with sorafenib in BCLC stage C advanced HCC.

This was a single-arm phase II trial (ChiCTR2100041874) with a Simon's two-stage design. Eligible patients were given a maximum of 6 cycles of hepatic artery infusion with FOLFOX chemotherapy plus camrelizumab (200 mg once every 3 weeks). Sorafenib (400 mg orally twice daily) was given since day 3 after the completion of the first cycle of hepatic artery infusion until disease progression, intolerable toxicity, or conversion to surgical resection. The primary endpoint was objective response rate (ORR) based on the modified Response Evaluation Criteria In Solid Tumors (mRECIST).

Between January 4, 2021, and December 11, 2023, 25 patients were enrolled. Eleven patients had partial response, with an ORR of 44.0% (95% CI, 24.6-63.5%). The primary endpoint was not met, and the study failed to enter the second stage. Median progression-free survival was 4.87 months (95% CI, 2.07-7.66), with a 12-month rate of 23.2%. Median overall survival was 8.87 months (95% CI, 8.17-9.57), with 12- and 24-month rates of 40.3% and 26.9%, respectively. Two (8.0%) patients received curative resection after the study treatment. Grade ≥ 3 treatment-related adverse events occurred in 19 (76.0%) patients, with the most common being decreased lymphocyte count (13 [52.0%]), increased aspartate aminotransferase (11 [44.0%]), and increased alanine aminotransferase (seven [28.0%]).

Hepatic artery infusion of FOLFOX chemotherapy plus camrelizumab combined with oral sorafenib shows manageable safety profile but modest antitumor activity in patients with BCLC stage C advanced HCC.

Immune checkpoint blockade, particularly targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), shows promise in treating hepatocellular carcinoma (HCC). However, acquired resistance, especially in patients with 'hot tumours', limits sustained benefits. Lysine-specific demethylase 1 (LSD1) plays a role in converting 'cold tumours' to 'hot tumours', but its involvement in PD-1 inhibitor resistance in HCC is unclear.

LSD1 and PD-L1 expression, along with CD8+ T cell infiltration, were assessed using immunohistochemistry in HCC tissues, correlating these markers with patient prognosis. The impact of LSD1 deletion on tumour cell proliferation and CD8+ T cell interactions was examined in vitro. Mouse models were used to study the combined effects of LSD1 inhibition and anti-PD-1 therapy on tumour growth and the tumour microenvironment (TME). The clinical relevance of LSD1, CD74 and effector CD8+ T cells was validated in advanced HCC patients treated with PD-1 blockade.

LSD1 overexpression in HCC patients correlated with reduced PD-L1 expression, less CD8+ T cell infiltration and poorer prognosis. LSD1 deletion increased PD-L1 expression, boosted effector CD8+ T cells in vitro and inhibited tumour growth in vivo. While anti-PD-1 monotherapy initially suppressed tumour growth, it led to relapse upon antibody withdrawal. In contrast, combining LSD1 inhibition with anti-PD-1 therapy effectively halted tumour growth and prevented relapse, likely through TME remodelling, enhanced CD8+ T cell activity and improved CD74-mediated antigen presentation. Clinically, low LSD1 expression was associated with better response to anti-PD-1 therapy.

LSD1 deletion reshapes the TME, enhances CD8+ T cell function and prevents acquired resistance to anti-PD-1 therapy in HCC. The combination of LSD1 inhibitors and PD-1 blockade offers a promising strategy for overcoming resistance in advanced HCC.

Uncovering the synthetic lethality resulting from LSD1 deletion and PD1 inhibitor co-administration, evaluating their combined effects on tumour growth and TME remodelling. Elucidating the mechanism underlying the combined therapy of LSD1 deletion with PD1 inhibition for HCC. Exploring the implications of LSD1, CD74 and effector CD8+ T cell expression levels in advanced HCC patients undergoing anti-PD1 treatment.

Currently, there is a lack of effective adjuvant therapies for patients at high-risk of recurrent hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) after radical resection. Given the efficacy of anti-programmed death 1/anti-programmed death ligand 1 plus anti-vascular endothelial growth factor receptor agents in advanced HCC, we conducted this study to investigate the efficacy of this combination regimen in the postoperative adjuvant treatment of patients with HBV-HCC.

To evaluate the value of postoperative combined therapy (PCT) with anti-programmed death 1/anti-programmed death ligand 1 and anti-vascular endothelial growth factor receptor agents in patients with HBV-HCC.

Patients with HBV-HCC who underwent radical resection surgery at Anhui Provincial Hospital Affiliated to Anhui Medical University between July 2020 and April 2023 were included. Recurrence-free survival (RFS) and overall survival were assessed using propensity score matching and inverse probability of treatment weighting. Cox regression analysis was used to identify factors affecting recurrence, and subgroup analysis was conducted to investigate the impact of medications on different populations. Treatment-related adverse events and liver function measurements were evaluated.

A total of 150 patients were recruited, of whom 30 underwent PCT and 120 did not. After adjusting for confounders, patients who underwent PCT had better RFS at 6 and 12 months than those who did not (P > 0.05). Similar results were observed in the Kaplan-Meier curves after propensity score matching or inverse probability of treatment weighting, although the difference was not statistically significant (P > 0.05). A maximum diameter of > 5 cm, vascular invasion, satellite nodules, and high gamma-glutamyl transferase levels were independent risk factors for recurrence (P < 0.05). No significant interaction effects were observed in subgroup analyses. The most prevalent adverse event was hypertension (66.7%). PCT was associated with an increased risk of hepatic impairment which may predict RFS rates (P = 0.041).

The recurrence rate was not significantly reduced in patients who underwent PCT. Hepatic impairment during treatment may indicate recurrence, and close monitoring of liver function and HBV infection is recommended.

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.

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.

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.

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.

Hepatocellular carcinoma (HCC) is increasing in prevalence globally, and cure remains limited with non-operative treatment. Surgical intervention, through resection or transplantation, offers a potential for cure for select patients. However, many patients present with advanced or unresectable disease, and recurrence rates remain high. Recent advances in systemic therapies, particularly immune checkpoint inhibitors, have demonstrated promise in treating unresectable HCC and as adjuvant therapy. Evidence from adjuvant trials highlights the synergistic potential of combined liver-directed and systemic therapies. These findings have ignited growing interest in neoadjuvant therapy across various scenarios: (1) as a bridging strategy while awaiting transplantation, (2) for downstaging disease to enable transplantation, (3) for converting unresectable disease to a resectable state, or (4) as neoadjuvant treatment in operable cases. Early-stage trials of neoadjuvant therapy in resectable HCC have reported promising outcomes. To realize the potential of neoadjuvant treatment for HCC, thoughtfully designed, adequately powered, multi-center clinical trials are essential.

Lenvatinib is the standard first-line therapy for advanced hepatocellular carcinoma (HCC), but drug resistance significantly hampers its efficacy. Increasing evidence has shown that circular RNAs (circRNAs) play critical roles in HCC pathogenesis. However, the underlying mechanisms of lenvatinib sensitivity regulated by circRNAs remain largely unclear. The present study aims to identify circRNAs involved in lenvatinib resistance, as well as to elucidate the underlying mechanisms. High-throughput sequencing revealed that hsa_circ_0000235 (circCCNY) was downregulated in matched HCC tumor tissues and lenvatinib-resistant cells. Both in vitro and in vivo experiments revealed that downregulation of circCCNY could induce lenvatinib resistance in HCC cells. Subsequently, RNA pull-down, mass spectrometry, and RNA immunoprecipitation techniques were employed to investigate the interactions between circCCNY, HSP60, and the E3 ubiquitin ligase SMURF1. Briefly, circCCNY bounds to HSP60, subsequently leading to HSP60 ubiquitination and degradation through its interaction with the E3 ubiquitin ligase SMURF1. As a result, HSP60 degradation released Raf kinase inhibitor protein (RKIP), leading to the inactivation of the MAPK signaling pathway, and subsequently enhanced the anti-tumor effect of lenvatinib against HCC. Moreover, we also demonstrated that circCCNY could enhance CD8+ T-cell infiltration and suppress immune evasion through inhibiting the MAPK/c-Myc/PD-L1 signaling pathway. Our findings revealed that circCCNY enhances HCC sensitivity to lenvatinib and suppresses immune evasion by inhibiting the MAPK signaling pathway in HCC. This suggests that circCCNY could serve as a promising therapeutic target in HCC treatment and a potential biomarker for predicting HCC sensitivity to lenvatinib.

Hepatocellular carcinoma (HCC) is an inflammation-associated tumor with a dismal prognosis. Immunotherapy has become an important treatment strategy for HCC, as immunity is closely related to inflammation in the tumor microenvironment. Inflammation regulates the expression of programmed death ligand-1 (PD-L1) in the immunosuppressive tumor microenvironment and affects immunotherapy efficacy. Interleukin-17A (IL-17A) is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors. We hypothesized that IL-17A participates in tumor progression by affecting the level of immune checkpoint molecules in HCC.

To investigate the effect and mechanism of action of IL-17A on PD-L1 expression and to identify attractive candidates for the treatment of HCC.

The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR, western blotting, and flow cytometry. Mechanistic studies were conducted with gene knockout models and pathway inhibitors. The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells. The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro, and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.

IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner, whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A. IL-17A enhanced the survival of HCC cells in the coculture system. IL-17A increased the viability, G2/M ratio, and migration of HCC cells and decreased the apoptotic index. Cyclin D1, VEGF, MMP9, and Bcl-1 expression increased after IL-17A treatment, whereas BAX expression decreased. The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8 + T lymphocyte infiltration in an HCC mouse model.

IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapentaplegic 2 signaling pathway in HCC cells. Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.

Immunotherapy has shown significant improvement in the survival of patients with hepatocellular carcinoma (HCC) compared to TKIs as first-line treatment. Unfortunately, approximately 30% of HCC exhibits intrinsic resistance to ICIs, making new therapeutic combinations urgently needed. The dysregulation of the Notch signaling pathway observed in HCC can affect immune cell response, reducing the efficacy of cancer immunotherapy. Here, we provide an overview of how Notch signaling regulates immune responses and present the therapeutic rationale for combining Notch signaling inhibition with ICIs to improve HCC treatment. Moreover, we propose using exosomes as non-invasive tools to assess Notch signaling activation in hepatic cancer cells, enabling accurate stratification of patients who can benefit from combined strategies.

Hepatocellular carcinoma (HCC) comprises the majority of primary liver cancers and possesses a low 5-year survival rate when in the advanced stages. Anillin (ANLN), a key player in cell growth and cytokinesis, is implicated in HCC development. Currently, no treatment agents are known to suppress ANLN. Analysis of The Cancer Genome Atlas data showed that high ANLN expression is associated with poor prognosis and survival in HCC patients. ANLN knockdown was shown to inhibit proliferation, cell cycle progression, and PD-L1 expression in liver cancer cells. The antipsychotic drug penfluridol was identified to suppress ANLN expression in the Connectivity Map analysis. Penfluridol downregulated ANLN at both the mRNA and protein levels, leading to G2/M cell cycle arrest and reduced colony formation in liver cancer cells. Mechanistically, penfluridol inhibited the transcription factor MYC from binding to an E-box motif in the ANLN promoter. This process was mediated by penfluridol-induced upregulation of NRF2, which competitively bound and sequestered MYC away from the ANLN promoter. Penfluridol inhibited the interaction between NRF2 and KEAP1, increasing NRF2. In a syngeneic mouse model, penfluridol suppressed liver tumour growth accompanied by increased NRF2 and decreased MYC and ANLN expression. These findings suggest penfluridol can be applied as the first ANLN blocker to modulate the MYC/NRF2/KEAP1 axis.

Murine double minute 2 (MDM2) plays an essential role in the cell cycle, apoptosis, DNA repair, and oncogene activation through p53-dependent and p53-independent signaling pathways. Several preclinical studies have shown that MDM2 is involved in tumor immune evasion. Therefore, MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention. In recent years, immune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic. However, the effectiveness of a single agent is only approximately 20%-40%, which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins. Here, we reviewed the role of MDM2 in regulating the immune microenvironment, tumor immune evasion, and hyperprogression during immunotherapy. In addition, we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tumors with MDM2 overexpression or amplification. The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.

Background/Objectives: Cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) represent major primary liver cancers, affecting one of the most vital organs in the human body. T regulatory (Treg) cells play an important role in liver cancers through the immunosuppression of antitumor immune responses. The current study focuses on the characterization of circulating natural killer (NK) cells and T cell subsets, including Treg cells, in CCA and HCC patients, before and after surgical tumor resection, in order to understand the effect of tumor resection on the homeostasis of peripheral blood NK cells and T cells. Methods: Whole blood assays were performed to monitor immune alterations and the functional competence of circulating lymphocytes in a group of ten healthy individuals, eight CCA patients, and twenty HCC patients, before and one month after the surgical procedure, using flow cytometry, cell sorting, and qRT-PCR. Results: Before tumor resection, both HCC and CCA patients display increased percentages of CD8+ Treg cells and decreased frequencies of circulating CD4+ Treg cells. Notwithstanding, no functional impairment was detected on circulating CD4+ Treg cells, neither in CCA nor in HCC patients. Interestingly, the frequency of peripheral CD4+ Treg cells increased from 0.55% ± 0.49 and 0.71% ± 0.54 (in CCA and HCC, respectively) at T0 to 0.99% ± 0.91 and 1.17% ± 0.33 (in CCA and HCC, respectively) at T1, following tumor resection. Conclusions: Our results suggest mechanisms of immune modulation induced by tumor resection.

One of the most prevalent pathological types of Primary Liver Cancer (PLC) is the Hepatocellular Carcinoma (HCC) poses a global health issue. The high recurrence and metastasis rate of HCC, coupled with a low 5-year survival rate, result in a bleak prognosis. Exosomes, small extracellular vesicles released by various cells, contain diverse non-coding RNA molecules, including circular RNAs (circRNAs), which play a significant role in intercellular communication and can impact HCC progression. Studies have revealed the potential clinical applications of exosomal circRNAs as biomarkers and therapeutic targets for HCC. These circRNAs can be transferred via exosomes to nearby non-cancerous cells, thereby regulating HCC progression and influencing malignant phenotypes, such as cell proliferation, invasion, metastasis, and drug resistance. This review provides a comprehensive overview of the identified exosomal circRNAs, highlighting their potential as non-invasive biomarkers for HCC, and suggesting new perspectives for HCC diagnosis and treatment. The circRNA from exosomal organelles promotes metastasis and immune scape because of their unique chirality which is different from the Biomolecular Homochirality.

This meta-analysis was dedicated to evaluating the effectiveness and safety of Atezolizumab plus Bevacizumab (Atez/Bev) and Lenvatinib (LEN) as first-line systematic therapy for unresectable hepatocellular carcinoma (u-HCC).

The prospective protocol for this study was registered with the PROSPERO (Registration number: CRD42022356874). Literature searches were conducted in PubMed, EMBASE database Cochrane Library, and Web Science to determine all clinical controlled studies that reported Atez/Bev and LEN for treating u-HCC. We. evaluated as primary end-point overall survival (OS) and progression-free survival (PFS), as well as other outcomes such as tumor response and adverse events (AEs).Quality assessment and data extraction of studies were conducted independently by three reviewers. Mean difference (MD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a fixed-effects or random-effects model. The meta-analysis was performed with RevMan 5.3 software.

12 retrospective cohort studies (RCSs) involving a total of 4948 patients were finally included. The results showed that compared with LEN, Atez/Bev can improve the patient's PFS (HR = 0.80, 95% CI: 0.72 ~ 0.88; p < 0.0001) and reduce the rate of overall AEs (OR = 0.46 95% CI: 0.38 ~ 0.55, p < 0.00001) and grade ≥ 3 AEs (OR = 0.43; 95% CI: 0.36 ~ 0.51, p < 0.00001), while there is no difference between OS and treatment responses rate (objective response rate, disease control rate, complete response, partial response, progressive disease, and stable disease) between two groups. In addition, the subgroup analysis shows that Atez/Bev can promote the OS of patients with viral hepatitis. (HR = 0.79, 95% CI: 0.67 ~ 0.95; p = 0.01), while LEN has an advantage in improving OS in patients with Child-Pugh grade B liver function (HR = 1.98, 95% CI: 1.50 ~ 2.63; p < 0.00001).

Current evidence shows that compared with LEN, Atez/Bev has more advantages in PFS and safety in treating u-HCC and can improve the OS of patients with viral. LEN has advantages in improving the OS of patients with grade B liver function. However, more multicenter randomized controlled experiments are needed in the future to verify our results.

PAK4 and PD-L1 have been suggested as novel therapeutic targets in human cancers. Moreover, PAK4 has been suggested to be a molecule closely related to the immune evasion of cancers. Therefore, this study evaluated the roles of PAK4 and PD-L1 in the progression of osteosarcomas in 32 osteosarcomas and osteosarcoma cells. In human osteosarcomas, immunohistochemical positivity for the expression of PAK4 (overall survival, p = 0.028) and PD-L1 (relapse-free survival, p = 0.002) were independent indicators for the survival of patients in a multivariate analysis. In osteosarcoma cells, the overexpression of PAK4 increased proliferation and invasiveness, while the knockdown of PAK4 suppressed proliferation and invasiveness. The expression of PAK4 was associated with the expression of the molecules related to cell cycle regulation, invasion, and apoptosis. PAK4 was involved in resistance to apoptosis under a treatment regime with doxorubicin for osteosarcoma. In U2OS cells, PAK4 was involved in the stabilization of PD-L1 from ubiquitin-mediated proteasomal degradation and the in vivo infiltration of immune cells such as regulatory T cells and PD1-, CD4-, and CD8-positive cells in mice tumors. In conclusion, this study suggests that PAK4 is involved in the progression of osteosarcoma by promoting proliferation, invasion, and resistance to doxorubicin and stabilized PD-L1 from proteasomal degradation.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis in advanced stages. While therapies targeting the checkpoint molecules programmed cell death 1 (PD-1), its ligand PD-L1, and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized treatment in many cancers, the results in ACCs were heterogeneous.

Their expression in ACC has not been systematically studied and might explain the variable response to immune checkpoint inhibitors.

The expression of PD-1, PD-L1 and CTLA-4 was examined in 162 tumor samples from 122 patients with ACC by immunohistochemistry (threshold of >1%) and correlated with tumoral T lymphocyte infiltration and clinical endpoints. Finally, univariate and multivariate analyses of progression-free and overall survival were performed.

PD-1 and PD-L1 were expressed in 26.5% and 24.7% of samples, respectively, with low expression in most tumor samples (median positive cells: 2.1% and 21.7%). In contrast, CTLA-4 expression was observed in 52.5% of ACC with a median of 38.4% positive cells. Positive PD-1 expression was associated with longer progression-free survival (HR 0.50, 95% CI 0.25-0.98, P = .04) even after considering prognostic factors. In contrast, PD-L1 and CTLA-4 did not correlate with clinical outcome. Additionally, PD-1 and PD-L1 expression correlated significantly with the amount of CD3+, CD4+, FoxP3+, and CD8+ T cells.

The heterogeneous expression of PD1, PD-L1, and CTLA-4 in this large series of well-annotated ACC samples might explain the heterogeneous results of the immunotherapies in advanced ACC. In addition, PD-1 expression is a strong prognostic biomarker that can easily be applied in routine clinical care and histopathological assessment.

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.

Liver cancer, which most commonly manifests as hepatocellular carcinoma (HCC), is the sixth most common cancer in the world. In HCC, the immune system plays a crucial role in the growth and proliferation of tumor cells. HCC achieve immune escape through the tumor microenvironment, which significantly promotes the development of this cancer. Here, this article introduces and summarizes the functions and effects of regulatory T cells (Tregs) in the tumor microenvironment, highlighting how Tregs inhibit and regulate the functions of immune and tumor cells, cytokines, ligands and receptors, etc, thereby promoting tumor immune escape. In addition, it discusses the mechanism of CAR-T therapy for HCC and elaborate on the relationship between CAR-T and Tregs.

Glycosyltransferase-associated genes play a crucial role in hepatocellular carcinoma (HCC) pathogenesis. This study investigates their impact on the tumor microenvironment and molecular mechanisms, offering insights into innovative immunotherapeutic strategies for HCC.

We utilized cutting-edge single-cell and spatial transcriptomics to examine HCC heterogeneity. Four single-cell scoring techniques were employed to evaluate glycosyltransferase genes. Spatial transcriptomic findings were validated, and bulk RNA-seq analysis was conducted to identify prognostic glycosyltransferase-related genes and potential immunotherapeutic targets. MGAT1's role was further explored through various functional assays.

Our analysis revealed diverse cell subpopulations in HCC with distinct glycosyltransferase gene activities, particularly in macrophages. Key glycosyltransferase genes specific to macrophages were identified. Temporal analysis illustrated macrophage evolution during tumor progression, while spatial transcriptomics highlighted reduced expression of these genes in core tumor macrophages. Integrating scRNA-seq, bulk RNA-seq, and spatial transcriptomics, MGAT1 emerged as a promising therapeutic target, showing significant potential in HCC immunotherapy.

This comprehensive study delves into glycosyltransferase-associated genes in HCC, elucidating their critical roles in cellular dynamics and immune cell interactions. Our findings open new avenues for immunotherapeutic interventions and personalized HCC management, pushing the boundaries of HCC immunotherapy.

Brain cancers, particularly glioblastoma multiforme (GBM), are challenging health issues with frequent unmet aspects. Today, discovering safe and effective therapeutic modalities for brain tumors is among the top research interests. Immunotherapy is an emerging area of investigation in cancer treatment. Since immune checkpoints play fundamental roles in repressing anti-cancer immunity, diverse immune checkpoint inhibitors (ICIs) have been developed, and some monoclonal antibodies have been approved clinically for particular cancers; nevertheless, there are significant concerns regarding their efficacy and safety in brain tumors. Among the various tools to modify the immune checkpoints, phytochemicals show good effectiveness and excellent safety, making them suitable candidates for developing better ICIs. Phytochemicals regulate multiple immunological checkpoint-related signaling pathways in cancer biology; however, their efficacy for clinical cancer immunotherapy remains to be established. Here, we discussed the involvement of immune checkpoints in cancer pathology and summarized recent advancements in applying phytochemicals in modulating immune checkpoints in brain tumors to highlight the state-of-the-art and give constructive prospects for future research.

Hepatocellular carcinoma (HCC), the most prevalent malignancy of the digestive tract, is characterized by a high mortality rate and poor prognosis, primarily due to its initial diagnosis at an advanced stage that precludes any surgical intervention. Recent advancements in systemic therapies have significantly improved oncological outcomes for intermediate and advanced-stage HCC, and the combination of locoregional and systemic therapies further facilitates tumor downstaging and increases the likelihood of surgical resectability for initially unresectable cases following conversion therapies. This shift toward high conversion rates with novel, multimodal treatment approaches has become a principal pathway for prolonged survival in patients with advanced HCC. However, the field of conversion therapy for HCC is marked by controversies, including the selection of potential surgical candidates, formulation of conversion therapy regimens, determination of optimal surgical timing, and application of adjuvant therapy post-surgery. Addressing these challenges and refining clinical protocols and research in HCC conversion therapy is essential for setting the groundwork for future advancements in treatment strategies and clinical research. This narrative review comprehensively summarizes the current strategies and clinical experiences in conversion therapy for advanced-stage HCC, emphasizing the unresolved issues and the path forward in the context of precision medicine. This work not only provides a comprehensive overview of the evolving landscape of treatment modalities for conversion therapy but also paves the way for future studies and innovations in this field.

Immune checkpoint inhibitors (ICIs) are emerging treatments for advanced hepatocellular carcinoma (HCC); however, evidence has shown they may induce hyperprogressive disease via unexplained mechanisms.

In this study, we investigated the possible stimulative effect of ICIs on programmed cell death-ligand 1 (PD-L1)-harboring liver cancer cells under immunocompetent cell-free conditions.

The sarcomatous HAK-5 cell line displayed the highest expression of PD-L1 among 11 human liver cancer cell lines used in this study. HLF showed moderate expression, while HepG2, Hep3B, and HuH-7 did not show any. Moreover, sarcomatous HCC tissues expressed high levels of PD-L1. We observed approximately 20% increase in cell proliferation in HAK-5 cells treated with anti-PD-L1 antibodies, such as durvalumab and atezolizumab, for 48 h compared with that of those treated with the control IgG and the anti-PD-1 antibody pembrolizumab. No response to durvalumab or atezolizumab was shown in PD-L1-nonexpressing cells. Loss-of-function and gain-of-function experiments for PD-L1 in HAK-5 and HepG2 cells resulted in a significant decrease and increase in cell proliferation, respectively. Phosphorylated receptor tyrosine kinase array and immunoprecipitation revealed direct interactions between PD-L1 and AXL in tumor cells. This was stabilized by extrinsic anti-PD-L1 antibodies in a glycosylated PD-L1-dependent manner. Activation of AXL, triggering signal relay to the Akt and Erk pathways, boosted tumor cell proliferation both in vitro and in xenografted tumors in NOD/SCID mice.

Collectively, this suggests that anti-PD-L1 antibodies stimulate cell proliferation via stabilization of the PD-L1-AXL complex in specific types of liver cancer, including in HCC with mesenchymal components.

Therapeutic anti-PD-L1 antibodies promote cell proliferation by stabilizing the PD-L1-AXL complex in PD-L1-abundant neoplasms, including in HCC with mesenchymal components. Such a mechanism may contribute to the development of hyperprogressive disease.

As a key sensor of double-stranded DNA (dsDNA), cyclic GMP-AMP synthase (cGAS) detects cytosolic dsDNA and initiates the synthesis of 2'3' cyclic GMP-AMP (cGAMP) that activates the stimulator of interferon genes (STING). This finally promotes the production of type I interferons (IFN-I) that is crucial for bridging innate and adaptive immunity. Recent evidence show that several antitumor therapies, including radiotherapy (RT), chemotherapy, targeted therapies and immunotherapies, activate the cGAS-STING pathway to provoke the antitumor immunity. In the last decade, the development of STING agonists has been a major focus in both basic research and the pharmaceutical industry. However, up to now, none of STING agonists have been approved for clinical use. Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node (dLN), research on the optimal way to activate STING in tumor microenvironment (TME) appears to be a promising direction. Moreover, besides enhancing IFN-I signaling, the cGAS-STING pathway also plays roles in senescence, autophagy, apoptosis, mitotic arrest, and DNA repair, contributing to tumor development and metastasis. In this review, we summarize the recent advances on cGAS-STING pathway's response to antitumor therapies and the strategies involving this pathway for tumor treatment.

Liver cancer (LC) is the sixth most common disease and the third most common cause of cancer-related mortality. The WHO predicts that more than 1 million deaths will occur from LC by 2030. Hepatocellular carcinoma (HCC) is a common form of primary LC. Today, the management of LC involves multiple disciplines, and multimodal therapy is typically selected on an individual basis, considering the intricate interactions between the patient's overall health, the stage of the tumor, and the degree of underlying liver disease. Currently, the treatment of cancers, including LC, has undergone a paradigm shift in the last ten years because of immuno-oncology. To treat HCC, immune therapy approaches have been developed to enhance or cause the body's natural immune response to specifically target tumor cells. In this context, immune checkpoint pathway inhibitors, engineered cytokines, adoptive cell therapy, immune cells modified with chimeric antigen receptors, and therapeutic cancer vaccines have advanced to clinical trials and offered new hope to cancer patients. The outcomes of these treatments are encouraging. Additionally, treatment using stem cells is a new approach for restoring deteriorated tissues because of their strong differentiation potential and capacity to release cytokines that encourage cell division and the formation of blood vessels. Although there is no proof that stem cell therapy works for many types of cancer, preclinical research on stem cells has shown promise in treating HCC. This review provides a recent update regarding the impact of immunotherapy and stem cells in HCC and promising outcomes.

Long non-coding RNAs (lncRNAs) are multifunctional and participate in a variety of biological processes and gene regulatory networks. The deregulation of lncRNAs has been extensively implicated in diverse human diseases, especially in cancers. Overwhelming evidence demonstrates that lncRNAs are essential to the pathophysiological processes of ovarian cancer (OC), acting as regulators involved in metastasis, cell death, chemoresistance, and tumor immunity. In this review, we illustrate the expanded functions of lncRNAs in the initiation and progression of OC and elaborate on the signaling pathways in which they pitch. Additionally, the potential clinical applications of lncRNAs as biomarkers in the diagnosis and treatment of OC were emphasized, cementing the bridge of communication between clinical practice and basic research.

Hepatitis B virus (HBV) infection generally elicits weak type-I interferon (IFN) immune response in hepatocytes, covering the regulatory effect of IFN-stimulated genes. In this study, low level of IFN-stimulated gene 12a (ISG12a) predicted malignant transformation and poor prognosis of HBV-associated hepatocellular carcinoma (HCC), whereas high level of ISG12a indicated active NK cell phenotypes. ISG12a interacts with TRIM21 to inhibit the phosphorylation activation of protein kinase B (PKB, also known as AKT) and β-catenin, suppressing PD-L1 expression to block PD-1/PD-L1 signaling, thereby enhancing the anticancer effect of NK cells. The suppression of PD-1-deficient NK-92 cells on HBV-associated tumors was independent of ISG12a expression, whereas the anticancer effect of PD-1-expressed NK-92 cells on HBV-associated tumors was enhanced by ISG12a and treatments of atezolizumab and nivolumab. Thus, tumor intrinsic ISG12a promotes the anticancer effect of NK cells by regulating PD-1/PD-L1 signaling, presenting the significant role of innate immunity in defending against HBV-associated HCC.

Hepatocellular carcinoma (HCC) is a highly aggressive form of liver cancer with poor prognosis. The lack of reliable biomarkers for early detection and accurate diagnosis and prognosis poses a significant challenge to its effective clinical management. In this study, we investigated the diagnostic and prognostic potential of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in peripheral blood mononuclear cells (PBMCs) in HCC. PD-1 and CTLA-4 gene expression was analyzed comparatively using PBMCs collected from HCC patients and healthy individuals. The results revealed higher PD-1 gene expression levels in patients with multifocal tumors, lymphatic invasion, or distant metastasis than those in their control counterparts. However, conventional serum biomarkers of liver function do not exhibit similar correlations. In conclusion, PD-1 gene expression is associated with OS and PFS and CTLA-4 gene expression is associated with OS, whereas the serum biomarkers analyzed in this study show no significant correlation with survival in HCC. Hence, PD-1 and CTLA-4 expressed in PBMCs are considered potential prognostic biomarkers for patients with HCC that can facilitate prediction of malignancy, response to currently available HCC treatments, and overall survival.

Approximately 90% of pancreatic cancer (PC) contain KRAS mutations. Mutated KRAS activates the downstream oncogenic PI3K/AKT and MEK signaling pathways and induces drug resistance. However, targeting both pathways with different drugs can also lead to excessive toxicity. ONC201 is a dual PI3K/AKT and MEK pathway inhibitor with an excellent safety profile that targets death receptor 5 (DR5) to induce apoptosis. Gemcitabine (GEM) is a first-line chemotherapy in PC, but it is metabolically unstable and can be stabilized by a prodrug approach. In this study, phospho-Akt, phospho-mTOR, and phospho-ERK protein expressions were evaluated in patient PDAC-tissues (n = 10). We used lipid-gemcitabine (L_GEM) conjugate, which is more stable and enters the cells by passive diffusion. Further, we evaluated the efficacy of L_GEM and ONC201 in PC cells and "KrasLSL-G12D; p53LoxP; Pdx1-CreER (KPC) triple mutant xenograft tumor-bearing mice. PDAC patient tissues showed significantly higher levels of p-AKT (Ser473), p-ERK (T202/T204), and p-mTOR compared to surrounding non-cancerous tissues. ONC201 in combination with L_GEM, showed a superior inhibitory effect on the growth of MIA PaCa-2 cells. In our in-vivo study, we found that ONC201 and L_GEM combination prevented neoplastic proliferation via AKT/ERK blockade to overcome chemoresistance and increased T-cell tumor surveillance. Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate the effect of GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.

Despite the promising results of immunotherapy, further experiments need to be considered because of several factors ranging from physical barriers to off-tumor adverse effects. It is surprising that adoptive cellular immunotherapy, particularly dendritic cell and cytokine-induced killer (DC-CIK) therapy, is far less emphasized in the treatment of cancer diseases. DC-CIK therapy in cancer patients presents auspicious results with low or no side effects, which should not be overlooked. More interestingly, almost all DC-CIK clinical trials are ongoing in China that highlight the limitations of therapeutic strategies and require large-scale research. To date, it is advisable to consider combination therapy with chemotherapy since it has shown promising outcomes with higher efficacy. In this article, the efficacy of DC-CIK therapy in patients with cancer is summarized by underscoring the lack of experiments on soft cancers on an unprecedented scale. In brief, DC-CIK therapy is a safe and effective therapeutic agent for malignant and nonmalignant diseases that enhances short-term and long-term effects.

Upregulation of TGFβ and Cox2 in the tumor microenvironment results in blockade of T-cell penetration into the tumor. Without access to tumor antigens, the T-cell response will not benefit from administration of the immune checkpoint antibodies. We created an intravenous polypeptide nanoparticle that can deliver two siRNAs (silencing TGFβ and Cox2). Systemic administration in mice, bearing a syngeneic orthotopic hepatocellular carcinoma (HCC), delivers the siRNAs to various cells in the liver, and significantly reduces the tumor. At 2 mg/kg (BIW) the nanoparticle demonstrated a single agent action and induced tumor growth inhibition to undetectable levels after five doses. Reducing the siRNAs to 1mg/kg BIW demonstrated greater inhibition in the presence of PD-L1 mAbs. After only three doses BIW, we could still recover a smaller tumor and, in tumor sections, showed an increase in penetration of CD4+ and CD8+ T-cells deeper into the remaining tumor that was not evident in animals treated with non-silencing siRNA. The combination of TGFβ and Cox2 siRNA co-administered in a polypeptide nanoparticle can act as a novel therapeutic alone against HCC and may augment the activity of the immune checkpoint antibodies. Silencing TGFβ and Cox2 converts an immune excluded (cold) tumor into a T-cell inflamed (hot) tumor.

Indoleamine-2,3-dioxygenase (IDO) helps orchestrate immune suppression and checkpoint inhibitor resistance in hepatocellular carcinoma (HCC). BMS-986,205 is a novel oral drug that potently and selectively inhibits IDO. This Phase I/II study evaluated the safety and tolerability of BMS-986,205 in combination with nivolumab as first-line therapy in advanced HCC.

Adults with untreated, unresectable/metastatic HCC received BMS-986,205 at two dose levels (50-100 mg orally daily) in combination with fixed dose nivolumab (240mg/m2 IV on Day 1 of each 14-day cycle). The primary objective was to determine the safety and tolerability of this combination; secondary objectives were to obtain preliminary efficacy.

Eight patients received a total of 91 treatment cycles in the dose escalation phase. All patients were Child Pugh A and 6 patients had underlying viral hepatitis. In the 6 evaluable patients, no dose-limiting toxicities (DLTs) were observed. The most common treatment-related adverse events (TRAEs) were aspartate transaminase (AST) and alanine transaminase (ALT) elevation (3 patients) and diarrhea, maculopapular rash and increased alkaline phosphatase (2 patients each). Grade 3 events were diarrhea and AST elevation (1 patient), and hyperglycemia and pancreatitis requiring treatment discontinuation (1 patient). No grade 4-5 events occurred. Partial response was observed in 1 patient (12.5%) and stable disease in 3 patients (37.5%), yielding a disease control rate of 50%. Median PFS was 8.5 weeks; median OS was not reached.

Combination BMS-986,205 and nivolumab showed a manageable safety profile with durable benefit as first-line therapy in a meaningful subset of advanced HCC patients.

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality worldwide. Programmed cell death ligand-1 (PD-L1) is an immune checkpoint protein that binds to programmed cell death-1 (PD-1), which is expressed in activated T cells and other immune cells and has been employed in cancer therapy, including HCC. Recently, PD-L1 overexpression has been documented in treatment-resistant cancer cells. Sorafenib is a multikinase inhibitor and the only FDA-approved treatment for advanced HCC. However, several patients exhibit resistance to sorafenib during treatment. This study aimed to assess the effect of glucose deprivation on PD-L1 expression in HCC cells. We used PD-L1-overexpressing HepG2 cells and IFN-γ-treated SK-Hep1 cells to explore the impact of glycolysis on PD-L1 expression. To validate the correlation between PD-L1 expression and glycolysis, we analyzed data from The Cancer Genome Atlas (TCGA) and used immunostaining for HCC tissue analysis. Furthermore, to modulate PD-L1 expression, we treated HepG2, SK-Hep1, and sorafenib-resistant SK-Hep1R cells with rapamycin. Here, we found that glucose deprivation reduced PD-L1 expression in HCC cells. Additionally, TCGA data and immunostaining analyses confirmed a positive correlation between the expression of hexokinase II (HK2), which plays a key role in glucose metabolism, and PD-L1. Notably, rapamycin treatment  decreased the expression of PD-L1 and HK2 in both high PD-L1-expressing HCC cells and sorafenib-resistant cells. Our results suggest that the modulation of PD-L1 expression by glucose deprivation may represent a strategy to overcome PD-L1 upregulation in patients with sorafenib-resistant HCC.