Liver cancer, more specifically hepatocellular carcinoma (HCC), is a global health issue and one of the dominant causes of cancer death around the world. In the past few decades, remarkable advances have been achieved in the systemic therapy of HCC. Immune checkpoint inhibitors (ICIs) have become a therapy mainstay for advanced HCC and have shown promise in the neoadjuvant therapy before resection. Despite these significant advancements, the compositions and functions of the immune system occur various alterations with age, called "immunosenescence", which may affect the antitumor effects and safety of ICIs, thus raising concerns that immunosenescence may impair elderly patients' response to ICIs. Therefore, it is important to learn more about the immunosenescence characteristics of elderly patients. However, the real-world elderly HCC patients may be not accurately represented by the elderly patients included in the clinical trials, affecting the generalizability of the efficacy and safety profiles from the clinical trials to the real-world elderly patients. This review summarizes the characteristics of immunosenescence and its influence on HCC progression and immunotherapy efficacy as well as provides the latest progress in ICIs available for HCC and discusses their treatment efficacy and safety on elderly patients. In the future, more studies are needed to clarify the mechanisms of immunosenescence in HCC, and to find sensitive screening tools or biomarkers to identify the patients who may benefit from ICIs.

Hepatobiliary malignancies encompass a spectrum of invasive carcinomas arising in the liver [hepatocellular carcinoma (HCC), bile ducts [intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (EHC)] and the gallbladder. These malignancies represent a growing global health burden, with rising incidence and mortality rates and their overall prognosis remains poor because many patients present with advanced unresectable disease at diagnosis. In recent years, significant advancements in understanding HCC immunogenicity have reshaped the therapeutic scenario of advanced HCC with the immunotherapy revolutionizing the current HCC treatment landscape and patients' prognosis. Moreover, the addition of immunotherapy to chemotherapy has recently established a new standard of care first-line treatment for patients with biliary tract cancers (BTCs) who had historically few therapeutic options. Currently, immunotherapy and immune checkpoint inhibitor (ICI)-based regimens stand as a valuable and practice-changing options in both HCC and BTC management. The mounting recent evidence supporting immunotherapy's survival benefit demands clinicians to stay updated with a rapidly evolving treatment landscape as well as gain knowledge about patient selection, response rate compared with other systemic treatments and immune-mediated adverse events (imAEs) management. A panel of international Experts, comprising hepatologists and oncologists, gathered to explore the challenges in effectively integrating immunotherapy in routine clinical practice. The aim of this review is to present the Experts' insights to inform treatment choice in HCC and BTC with a special emphasis on the role of currently available ICI-based therapies in shifting treatment paradigms and potentially reversing the natural course of these two deadly malignancies.

Combination therapy of anti-PD-1 plus lenvatinib has shown effective anti-tumour effects for unresectable hepatocellular carcinoma (HCC), but the overall prognosis of HCC is still unsatisfactory. Elucidating the molecular mechanism underlying HCC progression contributes to develop new effective treatment in order to enhances the response of anti-PD-1 plus lenvatinib therapy and improve the patients prognosis.

Here, we reported that targeting SAMD1 in HCC cells via small interference RNA-containing ZIF-90@HA (ATP/acid-responsive) Nanoparticles (ZIF-90@siRNA@HA NPs, ZSH NPs) significantly enhanced the anti-tumour effects of anti-PD-1 plus lenvatinib in vivo. Targeting SAMD1 in HCC cells not only increased cellular ROS abundance by inhibiting glycolysis and enhancing oxidative phosphorylation (OXPHOS) to increase ferroptosis sensitivity, but also inhibited the expression of CCL28, thereby reducing the recruitment of Treg cells, and improving the immunosuppression of tumour microenvironment. Mechanistically, SAMD1 suppression inhibits the expression of NUAK2 via Hippo pathway, thereby decreasing the phosphorylation of PFKP Ser386 and promoting the ubiquitination degradation of PFKP in HCC. Further study demonstrated that SAMD1 inhibition increased the expression of ITIH5 by regulating H3K4me3 demethylation at the ITIH5 promoter and then regulates Hippo pathway.

Our study revealed the potential application of targeting SAMD1 in HCC treatment by enhancing ferroptosis sensitivity and immune response.

This study aims to develop and validate a novel radiomics model utilizing magnetic resonance imaging (MRI) to predict progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (uHCC) who are receiving a combination of immune checkpoint inhibitors (ICIs) and antiangiogenic agents. This is an area that has not been previously explored using MRI-based radiomics.

111 patients with uHCC were enrolled in this study. After performing univariate cox regression and the least absolute shrinkage and selection operator (LASSO) algorithms to extract radiological features, the Rad-score was calculated through a Cox proportional hazards regression model and a random survival forest (RSF) model. The optimal calculation method was selected by comparing the Harrell's concordance index (C-index) values. The Rad-score was then combined with independent clinical risk factors to create a nomogram. C-index, time-dependent receiver operating characteristics (ROC) curves, calibration curves, and decision curve analysis were employed to assess the forecast ability of the risk models.

The combined nomogram incorporated independent clinical factors and Rad-score calculated by RSF demonstrated better prognosis prediction for PFS, with C-index of 0.846, 0.845, separately in the training and the validation cohorts. This indicates that our model performs well and has the potential to enable more precise patient stratification and personalized treatment strategies. Based on the risk level, the participants were classified into two distinct groups: the high-risk signature (HRS) group and the low-risk signature (LRS) group, with a significant difference between the groups (P < 0.01).

The effective clinical-radiomics nomogram based on MRI imaging is a promising tool in predicting the prognosis in uHCC patients receiving ICIs combined with anti-angiogenic agents, potentially leading to more effective clinical outcomes.

Liver cancer remains a major global health challenge, characterized by high mortality and limited treatment efficacy. Conventional therapies, including chemotherapy, immunotherapy, and viral vectors, are hindered by systemic toxicity, drug resistance, and high costs. Silica nanoparticles (SiO2NPs) have emerged as promising platforms for liver cancer therapy, offering precise drug delivery, stimuli-responsive release, and integrated diagnostic-therapeutic capabilities. This review critically examines the potential of SiO2NPs to overcome these therapeutic limitations. Notable advances include their high drug-loading capacity, customizable surface modifications, and dual-responsive systems (pH/redox/NIR-II) that enable >90% tumor-specific drug release. Preclinical studies have demonstrated synergistic efficacy in combination therapies. Additionally, theranostic SiO2NPs enable MRI-guided tumor delineation and real-time treatment monitoring. Despite promising results, challenges remain in long-term biosafety, scalable synthesis, and regulatory compliance. Early-phase clinical trials, including those using NIR-II-responsive platforms, highlight their translational potential but underscore the need for further validation of toxicity profiles and manufacturing standards. Future research should focus on optimizing combinatory treatment strategies, scaling up production, and aligning with evolving regulatory frameworks. By bridging nanomaterial innovation with clinical applications, SiO2NPs offer unparalleled potential for advancing precision oncology in hepatocellular carcinoma.

The LEAP trial series examining the synergy of pembrolizumab and lenvatinib across various cancers has yielded mixed results, highlighting the need for a more detailed understanding of combination therapies. By learning from these trials, we aim to advance the clinical development of more effective combination strategies to improve patient outcomes.

Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.

The relationship between hepatocellular carcinoma (HCC) and gut microbiota has gained attention for its impact on HCC immunotherapy.

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.

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.

The focus is on translating these insights into personalized medicine to optimize ICIs responses and improve HCC treatment outcomes.

Overall survival (OS) is recommended as a gold standard endpoint but has some limitations. We aimed to finding more effective surrogate endpoints for advanced hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs).

Three online databases were searched for randomized control trials (RCTs) on HCC, published between January 2015 and July 2023, that evaluated ICIs and reported progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and OS. The correlation between the potential surrogate endpoints and OS was evaluated at the trial, arm, and patient levels. The prediction models were validated in single-arm or non-RCTs. Individual data were collected from a real-world (RW) cohort with advanced HCC underwent ICI monotherapy at three tertiary medical centers in China.

Ten RCTs (6023 participants) with 11 comparisons were included. PFS had a moderately significant association with OS (R2 = 0.50, p = 0.014). ORR, DCR, and OS showed weak correlations. On limiting the analysis to ICI monotherapy studies, the correlations of OS with PFS became stronger (R2 = 0.85, p = 0.02). The RW cohort also verified that PFS was closely related to OS when patient received with ICI monotherapy.

PFS are recommended as surrogate markers in patients with advanced HCC treated with ICI monotherapy.

This meta-analysis and trial sequential analysis (TSA) aimed to evaluate the efficacy and safety of triple therapy with tyrosine kinase inhibitors (TKIs) combined with transcatheter arterial chemoembolization (TACE) plus programmed death 1 (PD-1) inhibitors (T-T-P) and dual therapy with TKIs combined with TACE (T-T) for the treatment of advanced unresectable hepatocellular carcinoma (uHCC).

Literature related to the efficacy of TKIs combined with TACE plus PD-1 inhibitors in uHCC was searched using the Embase, PubMed, and Cocrane libraries. TSA was used to reduce false positive results due to random error.

Seventeen articles were included in this meta-analysis, including 2,561 patients. In the T-T-P group, OS [HR 0.45, 95% confidence interval (CI) 0.39-0.52; p = 0.000], PFS [HR 0.43, 95% CI 0.38 - 0.48; p = 0.000], were significantly prolonged compared to those in the T-T group; ORR (RR 1.59 [95% CI 1.39-1.81]; p = 0.000) and DCR (RR 1.26 [95% CI 1.15-1.37]; p = 0.000) were significantly higher. TSA analysis showed early results without further testing. Prognostic factor analysis demonstrated that portal vein tumor thrombus (PVTT) and extrahepatic metastasis were common independent risk factors for OS and PFS. Regarding grade 3/4 adverse events results showed no statistically significant differences in any of them.

Compared with T-T treatment group, the T-T-P treatment group exhibited a notable improvement in OS and PFS, particularly in cases of PVTT and extrahepatic metastasis. Furthermore, it can markedly enhance the ORR and DCR in patients with uHCC.

Recently, immune checkpoint inhibitors have been widely used in the treatment of advanced liver cancer. Immune checkpoints are a type of molecules that play an important role in the self-regulation of the immune system. In tumor immunity, their activation by immune checkpoints leads to the inhibition of effector lymphocyte activation or the mediation of cytotoxic T cell dysfunction, resulting in immune escape. These immune checkpoints include programmed death receptor 1 (PD-1) and its ligand PD-L1, as well as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and others. Immune checkpoint inhibitors block the interaction between immune checkpoint receptors and ligands, thereby relieving the immune suppression caused by immune checkpoints, and reactivating immune cells to exert antitumor effects. With the continuous progress of immunotherapy research, drugs targeting PDL-1, PD-1, and CTLA-4 have played an important role in clinical treatment. However, some patients still cannot benefit from immunotherapy; therefore, multitarget immunotherapy is an important way to improve the response rate of immunotherapy. CD96 is one of the members of the immunoglobulin superfamily receptors, which mainly functions by regulating natural killer cells and CD8+ T cells, and is expected to become a new generation of immune checkpoints. This article reviews the molecular structure of CD96, its role in tumor immunity, and its application in hepatocellular carcinoma, hoping to provide reference for related research.

Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.

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.

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.

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.

Hepatocellular carcinoma (HCC) poses a significant global burden as a highly prevalent and life-threatening malignant tumor that endangers human life and wellbeing. The purpose of this study was to examine how DNA methylation-driven genes impact the prognosis of HCC patients.

Differentially expressed genes from The Cancer Genome Atlas, GSE76427, GSE25097 and GSE14520 datasets were collected to perform differential expression analysis between HCC patients and controls. Weighted gene coexpression network analysis (WGCNA) was subsequently performed to create coexpression modules for the DEGs. Then, ssGSEA was employed to investigate the infiltration of immune cells in HCC. Enrichment analysis and methylation were carried out for the module genes. We utilized Kaplan-Meier survival analysis to assess patient prognosis.

Eight coexpression modules were identified via WGCNA for 1927 upregulated and 1,231 downregulated DEGs, after which the hub genes of the modules were identified. Module 5 had high immune infiltration, and the hub gene SCAMP3 was positively associated with Tcm. Module 3 exhibited a low level of immune infiltration, and the expression of the hub gene HCLS1 was negatively correlated with T cells and dendritic cells. Furthermore, we obtained five hub genes (BOP1, BUB1B, NOTCH3, SCAMP3, and SNRPD2) as methylation-driven genes. BOP1 and BUB1B were found to be correlated with unfavorable overall survival in patients with HCC.

HCLS1 and SCAMP3 are associated with immunity, whereas BOP1 and BUB1B are modified by methylation and may serve as prognostic markers for HCC.

Early symptoms of hepatocellular carcinoma (HCC) are not obvious, and more than 70% of which does not receive radical hepatectomy, when first diagnosed. In recent years, molecular-targeted drugs combined with immunotherapy and other therapeutic methods have provided new treatment options for middle and advanced HCC (aHCC). Predicting the effect of targeted combined immunotherapy has become a hot topic in current research.

To explore the relationship between nodule enhancement in hepatobiliary phase and the efficacy of combined targeted immunotherapy for aHCC.

Data from 56 patients with aHCC for magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid were retrospectively collected. Signal intensity of intrahepatic nodules was measured, and the hepatobiliary relative enhancement ratio (RER) was calculated. Progression-free survival (PFS) of patients with high and low reinforcement of HCC nodules was compared. The model was validated using receiver operating characteristic curves. Univariate and multivariate logistic regression and Kaplan-Meier analysis were performed to explore factors influencing the efficacy of targeted immunization and PFS.

Univariate and multivariate analyses revealed that the RER, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and prognostic nutritional index were significantly associated with the efficacy of tyrosine kinase inhibitors combined with immunotherapy (P < 0.05). The area under the curve of the RER for predicting the efficacy of tyrosine kinase inhibitors combined with anti-programmed death 1 antibody in patients with aHCC was 0.876 (95% confidence interval: 0.781-0.971, P < 0.05), the optimal cutoff value was 0.904, diagnostic sensitivity was 87.5%, and specificity was 79.2%. Kaplan-Meier analysis showed that neutrophil-to-lymphocyte ratio < 5, platelet-to-lymphocyte ratio < 300, prognostic nutritional index < 45, and RER < 0.9 significantly improved PFS.

AHCC nodules enhancement in the hepatobiliary stage was significantly correlated with PFS. Imaging information and immunological indicators had high predictive efficacy for targeted combined immunotherapy and were associated with PFS.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death and the sixth most prevalent cancer worldwide. However, most patients with HCC are at an advanced stage at the time of clinical diagnosis, making surgery impossible. In the past, targeted therapeutic drugs such as sorafenib and lenvatinib were the main treatments. With recent breakthroughs in medicine, immunotherapy, particularly immune checkpoint inhibitors (ICIs), has garnered interest and has been extensively studied for clinical treatment. In addition to single-agent therapies, combination regimens involving ICIs have also been developed. Despite this progress, not all patients with HCC benefit from immunotherapy. Therefore, to improve the treatment response rates, it is crucial to identify patients with HCC who are suitable for immunotherapy. The exploration and validation of markers to predict the outcomes of immunotherapeutic treatments in patients with HCC are of clinical importance. In this article, we provide a comprehensive review of research progress in immunotherapy, particularly ICIs and combination therapies, for HCC. Furthermore, we summarize the clinical indicators and tumor markers discovered in recent years to forecast immunotherapy outcomes in patients with HCC. We also outline predictive markers for the occurrence of immune-related adverse events in patients with HCC receiving immunotherapy and discuss future research directions in the immunotherapeutic treatment landscape.

Immune checkpoint inhibitors (ICIs) have been proved to have certain therapeutic effects for primary liver cancer. However, the efficacy and safety of their applications in liver transplantation (LT) recipients with recurrent tumor remained unclear and even controversial.

A retrospective study was conducted to evaluate the safety and efficacy of atezolizumab in LT recipients with recurrent PLC from August 1, 2019, to July 1, 2022. The primary endpoint was the incidence of allograft rejection, while secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Additionally, risk factors associated with ICI-related rejection were analyzed.

A total of eight LT recipients with recurrent PLC were included in the study, comprising six cases of hepatocellular carcinoma (HCC) and two cases of intrahepatic cholangiocarcinoma (ICC). The median number of atezolizumab treatment cycles was 3 (range, 1-10). Graft rejection occurred in 25% of patients (2/8). The median overall survival (mOS) from the initiation of atezolizumab was 6.2 months (range, 0.7-12.5 months), with a mortality rate of 75% (6/8). The ORR (complete response [CR] + partial response [PR]) was 28.5% (2/7), and the disease control rate (DCR; CR + PR + stable disease [SD]) was 42.9% (3/7). Time from LT to recurrence (P = 0.008) and Interval time from LT to atezolizumab (P = 0.005) were associated with liver rejection.

Atezolizumab demonstrated a certain degree of efficacy as a salvage treatment for patients with recurrent HCC and ICC after LT. However, given the potential risk of allograft rejection, careful evaluation of safety is essential before initiating ICI therapy. Moreover, close monitoring and timely intervention are necessary during treatment to mitigate the risk of rejection. Future studies should further explore the optimal timing and strategies for ICI administration in this patient population.

This study evaluated the effectiveness and safety of tislelizumab plus lenvatinib (TL group) and tislelizumab monotherapy (T group) in patients with stage C hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer (BCLC) staging system after lenvatinib failure, and it analyzed the factors influencing the effectiveness of TL as a second-line treatment. This retrospective analysis involved 51 patients treated at a single center between January 2019 and July 2023. Survival outcomes and tumor responses were compared between the TL and T monotherapy groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were identified using Cox proportional hazard regression models. Among patients with BCLC stage C advanced HCC who experienced lenvatinib treatment failure, median PFS was significantly longer in the TL group than in the T group (6.8 months vs. 4.5 months, p = 0.003), and OS was notably extended in the TL group (14.0 months vs. 10.4 months, p = 0.012). Although the disease control rate (64% vs. 53.8%, p = 0.461) and objective response rate (20% vs. 7.7%, p = 0.202) were numerically higher in the TL group, these differences did not reach significance. Child-Pugh B liver function and tislelizumab monotherapy were independent prognostic factors for poor OS, whereas only tislelizumab monotherapy was an independent prognostic factor for poor PFS, Child-Pugh B was not a prognostic factor for PFS. Subgroup analysis demonstrated the OS benefit of tislelizumab plus lenvatinib in patients with Child-Pugh A liver function (14.0 months vs. 12.0 months, p = 0.013) but not in those with Child-Pugh B liver function (7.7 months vs. 6.1 months, p = 0.225). In the TL group, the most frequent treatment-related adverse events (AEs) were hand-foot skin reaction (32%), hypertension (28%), diarrhea (32%), and hypothyroidism (20%). Grade 3 or higher AEs occurred in 24% of patients in the TL group, and hand-foot skin reaction and diarrhea were the most frequent grade 3 or higher AEs. The incidence of AEs was comparable between the two groups. As a second-line treatment, the combination of tislelizumab and lenvatinib was well tolerated and associated with improved OS and PFS versus tislelizumab alone for patients with advanced HCC, particularly in those with Child-Pugh A liver function.

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) remains one of the most prevalent and deadliest cancers. With the approval of multiple first- and second-line agents, especially the combination therapies based on immune checkpoint inhibitor (ICI) regimens, the landscape of systemic therapy for advanced HCC (aHCC) is more diverse than ever before. The efficacy of current systemic therapies shows great heterogeneity in patients with aHCC, thereby identifying biomarkers for response prediction and patient stratification has become an urgent need. The main biomarkers for systemic therapy in hepatocellular carcinoma are derived from peripheral blood, tissues, and imaging. Currently, the understanding of the clinical response to systemic therapy indicates unequivocally that a single biomarker cannot be used to identify patients who are likely to benefit from these treatments. In this review, we provide an integrated landscape of the recent development in molecular targeted therapies and ICIs-based therapies, especially focusing on the role of clinically applicable predictive biomarkers. Additionally, we further highlight the latest advancements in biomarker-driven therapies, including targeted treatments, adoptive cell therapies, and bispecific antibodies.

Immunotherapy targeting the programmed death-ligand 1 (PD-L1) pathway is a standard treatment for advanced hepatocellular carcinoma (HCC). The Wnt signaling pathway, often upregulated in HCC, contributes to an immunosuppressive tumor microenvironment. This study investigated the impact of Wnt pathway inhibition on PD-L1 expression in HCC and evaluated the potential therapeutic benefit of combining Wnt pathway inhibition with PD-L1 blockade.

The effects of Wnt pathway inhibitors XAV939 and IWR-1 on PD-L1 expression were examined in human HCC cell lines HuH7 and Hep3B. Beta-catenin overexpression and knockdown experiments confirmed these findings. For in vivo efficacy, the BNL 1ME A.7R.1 mouse HCC cell line was orthotopically implanted in mice, which were subsequently treated with XAV939, anti-PD-L1 antibodies, or both.

Wnt pathway inhibitors XAV939 and IWR-1 significantly reduced PD-L1 protein expression in a dose-dependent manner in HuH7 and Hep3B cells, without affecting mRNA levels. CTNNB1 knockdown produced similar results, and beta-catenin overexpression reversed the effects of Wnt pathway inhibitors on PD-L1 expression. Wnt pathway inhibition did not promote PD-L1 protein degradation but instead increased the level of unphosphorylated 4EBP1, which could prevent the translation function of eIF-4E. In vivo, mice treated with a combination of XAV939 and an anti-PD-L1 antibody had significantly smaller tumors compared to those treated with either agent alone. The combination treatment also enhanced multiple immune-related pathways in harvested tumors.

Inhibition of the Wnt pathway reduced PD-L1 expression in HCC cells and enhanced the efficacy of PD-L1 blockade, supporting its potential as HCC treatment.

Immunotherapy has revolutionized cancer treatment and complements traditional therapies, including surgery, chemotherapy, radiation therapy, and targeted therapies. Immunotherapy redirects the patient's immune system against tumors via several immune-mediated approaches. Over the past few years, therapeutic immunization, which enable the patient's T cells to better recognize and kill tumors, have been increasingly tested in the clinic, with several approaches demonstrating treatment improvements. There has been a renewed interest in cancer vaccines due to advances in tumor antigen identification, immune response optimization, novel adjuvants, next-generation vaccine delivery platforms, and antigen designs. The COVID-19 pandemic accelerated progress in nucleic acid-based vaccine manufacturing, which spurred broader interest in mRNA or plasmid platforms. Enhanced DNA vaccine designs, including optimized leader sequences and RNA and codon optimizations, improved formulations, and delivery via adaptive electroporation using stereotactic intramuscular/intradermal methods have improved T cell responses to plasmid-delivered tumor antigens. Additionally, advancements for direct in vivo delivery of DNA-encoded monospecific/bispecific antibodies offer novel tumor-targeting strategies. This review summarizes the recent clinical data for therapeutic cancer vaccines utilizing the DNA platform, including vaccines targeting common tumor-associated and viral antigens and neoantigen vaccines using nucleic acid technologies. We also summarize preclinical data using DNA-launched monoclonal/bispecific antibodies, underscoring their potential as a novel cancer therapy tool.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally. The tumor microenvironment (TME) plays a pivotal role in HCC progression, characterized by dynamic interactions between stromal components, immune cells, and tumor cells. Key immune players, including tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs), MDSCs, dendritic cells (DCs), and natural killer (NK) cells, contribute to immune evasion and tumor progression. Recent advances in immunotherapy, such as immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell therapy (ACT), and combination therapies, have shown promise in enhancing anti-tumor responses. Dual ICI combinations, ICIs with molecular targeted drugs, and integration with local treatments or radiotherapy have demonstrated improved outcomes in HCC patients. This review highlights the evolving understanding of the immune microenvironment and the therapeutic potential of immunotherapeutic strategies in HCC management.

Hepatocellular carcinoma (HCC) with MYC oncogene amplification remains a serious challenge in clinical practice. Recent advances in comprehensive treatment strategies, particularly the combination of radiotherapy and immunotherapy, offer new hope. To further improve efficacy while lowering radiation doses, nanopharmaceuticals based on high-Z elements have been extensively studied in radio-immunotherapy. In this work, a hafnium-based metal-organic framework (Hf-MOF), UiO-66-Hf(2OH)-CB-839/BSO@HA (UiO-66-Hf(2OH)-C/B@HA), was designed to codeliver telaglenastat (CB-839) and buthionine sulfoximine (BSO), which synergistically inhibited glutamine metabolism and alleviated tumor hypoxia. Further modification with hyaluronic acid (HA) enhanced tumor targeting, ultimately strengthening the efficacy of radiotherapy in MYC-amplified HCC. Beyond increasing reactive oxygen species (ROS) generation, promoting DNA damage, and inducing tumor apoptosis, more importantly, UiO66-Hf(2OH)-C/B@HA triggered immunogenic cell death (ICD), driving the antitumor immune response. Combination with immune checkpoint blockade (ICB) further enhanced the efficacy, accompanied by increased infiltration of T cells with high granzyme B expression (GZMB+ T cells) within the tumor microenvironment (TME). In the orthotopic HCC model, established with MYC-amplified tumor cells, intravenous administration of UiO66-Hf(2OH)-C/B@HA significantly potentiated the efficacy of radio-immunotherapy, resulting in superior tumor regression. In summary, our study provides insights into the design of Hf-MOF for radio-immunotherapy and proposes a promising therapeutic approach for MYC-amplified HCC.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high morbidity and mortality, as well as poor prognosis. Therefore, it is imperative to explore alternative therapeutic targets for HCC treatment. Ferroptosis and cuproptosis have recently been identified as metal-dependent cell death mechanisms that play significant roles in HCC treatment. This study identified potential cross-talk between ferroptosis and cuproptosis, including the common hub glutathione, common site of occurrence, mitochondria, shared epigenetic modification mode, RNA N6 methyladenosine modification, mutual inhibitor, nuclear factor erythroid 2-related factor 2, and dual regulator, p53. These findings provide a theoretical foundation for the joint induction of HCC cell death and effective inhibition of HCC progression. However, some immune cells are susceptible to ferroptosis or cuproptosis, which may impair or enhance anti-cancer immune function. We propose strategies to target specific targets molecules such as tripartite motif containing 25, ferroptosis suppressor protein 1, and peroxisome proliferator-activated receptor gamma or exploit the unique acidic environment surrounding cancer cells to precisely induce ferroptosis in cancer cells. This approach aims to advance the development of precision medicine for HCC treatment.

The tumor microenvironment (TME) plays a crucial role in the limited efficacy of existing treatments for hepatocellular carcinoma (HCC), with tumor-associated endothelial cells (TECs) serving as fundamental TME components that substantially influence tumor progression and treatment efficacy. However, the precise roles and mechanisms of TECs in HCC remain inadequately understood.

We employed a multi-omics profiling strategy to investigate the single-cell and spatiotemporal evolution of TECs within the microenvironment of HCC tumors, showcasing varied responses to immunotherapy. Through an analysis of a clinical cohort of patients with HCC, we explored the correlation between TEC subpopulations and immunotherapy outcomes. The influence of TEC subsets on the immune microenvironment was confirmed through comprehensive in vitro and in vivo studies. To further explore the mechanisms of distinct TEC subpopulations in microenvironmental modulation and their impact on immunotherapy, we utilized TEC subset-specific knockout mouse models as well as humanized mouse models.

In this study, we identified a new subset of CXCL12+ TECs that exert a crucial role in immune suppression within the HCC TME. Functionally, CXCL12+ TECs impede the differentiation of CD8+ naïve T cells into CD8+ cytotoxic T cells by secreting CXCL12. Furthermore, they attract myeloid-derived suppressor cells (MDSCs). A bispecific antibody was developed to target both CXCL12 and PD1 specifically, showing significant promise in bolstering anti-tumor immune responses and advancing HCC therapy.

CXCL12+ TECs are pivotal in mediating immunosuppression within the HCC microenvironment and targeting CXCL12+ TECs presents a promising approach to augment the efficacy of immunotherapies in patients with HCC.

This investigation reveals a pivotal mechanism wherein CXCL12+ tumor-associated endothelial cells (TECs) emerge as crucial modulators of immune suppression in the tumor microenvironment of hepatocellular carcinoma (HCC). The discovery of CXCL12+ TECs as inhibitors of CD8+ naïve T cell activation and recruiters of myeloid-derived suppressor cells significantly advances our grasp of the dynamic between HCC and immune regulation. Moreover, the development and application of a bispecific antibody precisely targeting CXCL12 and PD1 has proven to enhance immune responses in a humanized mouse HCC model. This finding underscores a promising therapeutic direction for HCC, offering the potential to amplify the impact of current immunotherapies.

The age-related decline in immunity appears to be associated not only with cancer development but also with differential responses to immune checkpoint inhibitors (ICIs). Despite their increasing utility across various malignancies and therapeutic settings, limited data -derived primarily from subgroup analyses of randomized controlled trials (RCTs), pooled meta-analyses, and retrospective studies- are available on the effects of aging on their efficacy and toxicity. Immunosenescence, characterized by the progressive decline of the function of the immune system, and inflammaging, a state of persistent low-grade sterile inflammation, may influence ICI outcomes. Additionally, the incidence, severity, and subtypes of immune-related adverse events (irAEs) may differ between older and younger individuals due to loss of immunotolerance. In the current review, starting from a a comprehensive discussion of the pathophysiology of immunosenescence, we proceed to critically review age-related retrospective and randomized evidence supporting FDA-approved ICIs. We highlight similarities or differences across age groups and the clinical benefit of ICIs in elderly versus younger cancer patients. The optimal integration of ICIs in geriatric oncology necessitates greater inclusion of this patient demographic in RCTs along with real-world data in order to acquire robust data which will guide evidence-based treatment decisions for this population.

Over the past years, there has been a remarkable advance in the systemic treatment options for advanced HCC. The overall survival has gradually increased over time, with larger benefits for patients with sensitive tumors and preserved liver function, the latter being an essential condition for the delivery of sequential lines of treatment and optimization of clinical outcomes. With the approval of new first-line agents and the introduction of immune checkpoint inhibitor-based therapies, the treatment landscape of advanced HCC is becoming wider than ever. Atezolizumab plus bevacizumab and, more recently, durvalumab plus tremelimumab have entered the clinical practice and are the current standard of care for treatment-naïve patients, surpassing sorafenib and lenvatinib monopoly. As no head-to-head comparisons are available among all the first-line treatment options, the recommendation for the most appropriate choice and sequence is patient-driven and integrates efficacy data with clinical comorbidities, background liver disease, and the safety profile of available drugs. In addition, predictive biomarkers for successful patients' stratification are yet to be available and constitute the focus of ongoing research. The treatment algorithm is likely to become even more complex since systemic therapeutic approaches are now being translated into earlier stages of the disease, with an impact on the evolution of the sequential treatment of patients with HCC.

Immune checkpoint inhibitors (ICIs) combined with anti-vascular endothelial growth factor (VEGF) have been the standard first-line treatment of hepatocellular carcinoma (HCC). However, the efficacy of this combination in post-line treatment is still unknown. This study aimed to evaluate the efficacy and safety of the combination of anti-PD-L1 envafolimab and novel humanized anti-VEGF suvemcitug as second-line treatment for patients with HCC.

This open-label, prospective phase II clinical study (NCT05148195) comprised safety run-in stage and dose expansion stage of HCC cohort. Eligible patients were aged ≥ 18 years and had undergone at least a prior line of treatment. Patients received fixed-dose envafolimab and suvemcitug until termination of disease progression, unacceptable toxicities, or withdrawal. The primary endpoint of safety run-in stage was recommended dose (RD), and dose expansion stage was objective response rate (ORR).

As of August 10, 2023, no dose-limiting toxicity was observed in six patients in the safety-run-in stage, and 2 mg/kg dose every 3 weeks was declared the RD of suvemcitug. Among 20 patients with HCC, the median age was 54.5 (range, 42-70) years. Of these patients, 20 (100.0%) received ≥ one prior line treatment, with 20 (100%) received tyrosine kinase inhibitor (TKI) treatment and 8 (40.0%) received prior ICI treatment. The ORR was 10.0% (95% confidence interval (CI), 1.2-31.7), DCR was 65.0% (95% CI, 40.8-84.6), and DoR was not reached (NR). With a median follow-up of 13.9 months, the median progression-free survival (PFS) and median overall survival (OS) were 4.3 months (95% CI, 1.4-8.1) and 10.7 months (95% CI, 6.0-not evaluable [NE]), respectively. Treatment-related adverse events (TRAEs) of grade ≥ 3 occurred in 40% patients, with proteinuria (20.0%, 4/20) being the most frequent. The ORR of no lung metastasis, prior first-line treatment and IO naïve treatment subgroup was 16.7%.

The combination of envafolimab and suvemcitug showed a tolerable safety profile and promising antitumor activity in HCC patients who failed later-line treatment.

Hepatocellular carcinoma (HCC) remains a major global health concern, as it is the most common primary liver cancer and the fourth leading cause of cancer-related mortality.

Immune checkpoint inhibitors (ICIs) have significantly shifted the treatment paradigm, offering promising survival outcomes. However, the controlled conditions of randomized clinical trials (RCTs) often fail to reflect real-world complexities, emphasizing the necessity for strong real-world evidence (RWE). RWE, in most cases derived from observational studies, provides critical insights into the effectiveness, safety, and tolerability of systemic therapies across diverse populations and settings. The authors searched MEDLINE, Ovid Embase, and Scopus for full-text published articles in any language from the inception to 30 June 2024.This review evaluates RWE on systemic therapies for advanced HCC, including tyrosine kinase inhibitors (TKIs) like sorafenib and lenvatinib, ICIs such as nivolumab and pembrolizumab, and combination therapies like atezolizumab/bevacizumab and durvalumab/tremelimumab.

Studies reveal discrepancies in treatment efficacy and adverse event profiles between RCTs and routine clinical practice, underscoring the need for individualized treatment strategies. RWE highlights the influence of liver disease etiology, liver function, and tumor burden on treatment outcomes, guiding therapy selection.