The emergence of immuno-oncology (IO) has led to revolutionary changes in the field of cancer treatment. Despite notable advancements in this field, a thorough exploration of its full depth and extent has yet to be performed. This study provides a comprehensive overview of publications pertaining to IO. Publications on IO from 2014 to 2023 were retrieved by searching the Web of Science Core Collection database (WoSCC). VOSviewer software and Citespace software were used for the visualized analysis. A total of 1,874 articles have been published in the IO domain. The number of publications and citations has been increasing annually. This study also examines the primary research directions within the field of IO. In conclusion, this study offers a comprehensive overview of the opportunities and challenges associated with IO, illuminating the current status of research and indicating potential future trajectories in this rapidly progressing field. This study provides a comprehensive survey of the current research status and hot spots within the field of IO. It will assist researchers in comprehending the current research emphasis and development trends in this field and offers guidance for future research directions.

The development of novel microspheres for the combination of sonodynamic therapy (SDT) with transarterial embolization (TAE) therapy to amplify their efficacy has received increasing attention. Herein, a novel strategy for encapsulating sonosensitizers (e.g., oxygen-deficient manganese tungstate (MnWOX) nanodots) with gelatin microspheres was proposed. The obtained MnWOX-encapsulated microspheres (abbr. Mn-GMSs) facilitated efficient sonodynamic-embolization-metalloimmune therapy via the immune effects of metal ions on orthotopic liver cancer tumor after transarterial embolization (TAE). Due to the strong cavitation effect caused by the porous structure, Mn-GMSs exhibited a greater reactive oxygen species (ROS) generation rate than the free MnWOX nanodots under US irradiation. Efficient SDT revealed robust cell-killing effects and triggered strong immunogenic cell death (ICD). Moreover, the Mn ions released from the bioactive Mn-GMSs further stimulated the dendritic cells (DCs) maturation and triggered the activation of the cGAS/STING pathway to enhance the immunological effect. Thus, Mn-GMSs achieved significant SDT therapeutic outcomes in H22 tumors in mice, and the combination of the Mn-GMSs triggered SDT with programmed cell death ligand 1 (PD-L1) antibodies could further enhance therapeutic outcomes. The Mn-GMSs exhibited high ROS generation efficacy under US irradiation, significant immune activation, good efficacy in combination with immune checkpoint inhibitor, and great potential for artery embolization-assisted drug delivery, thus enabling effective destruction of liver tumors in rats and rabbits. Therefore, this work provides a strategy for applying SDT in deep tumors and highlights a promising sonodynamic-embolization therapy for combating liver cancers.

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.

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.

Indirect mechanisms of cancer immunotherapies result in delayed treatment effects that vary among patients. Consequently, the use of the log-rank test in trial design and analysis can lead to significant power loss and pose additional challenges for interim decisions in adaptive designs. In this paper, we describe patients' survival using a piecewise proportional hazard model with random lag time and propose an adaptive promising zone design for cancer immunotherapy with heterogeneous delayed effects. We provide solutions for calculating conditional power and adjusting the critical value for the log-rank test with interim data. We divide the sample space into three zones - unfavourable, promising, and favourable -based on re-estimations of the survival parameters, the log-rank test statistic at the interim analysis, and the initial and maximum sample sizes. If the interim results fall into the promising zone, the sample size is increased; otherwise, it remains unchanged. We show through simulations that our proposed approach has greater overall power than the fixed sample design and similar power to the matched group sequential trial. Furthermore, we confirm that critical value adjustment effectively controls the type I error rate inflation. Finally, we provide recommendations on the implementation of our proposed method in cancer immunotherapy trials.

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.

Although cancer chemopreventive agents have been confirmed to effectively protect high-risk populations from cancer invasion or recurrence, only over ten drugs have been approved by the U.S. Food and Drug Administration. Therefore, screening potent cancer chemopreventive agents is crucial to reduce the constantly increasing incidence and mortality rate of cancer. Considering the lengthy prevention process, an ideal chemopreventive agent should be nontoxic, inexpensive, and oral. Natural compounds have become a natural treasure reservoir for cancer chemoprevention because of their superior ease of availability, cost-effectiveness, and safety. The benefits of natural compounds as chemopreventive agents in cancer prevention have been confirmed in various studies. In light of this, the present review is intended to fully delineate the entire scope of cancer chemoprevention, and primarily focuses on various aspects of cancer chemoprevention based on natural compounds, specifically focusing on the mechanism of action of natural compounds in cancer prevention, and discussing in detail how they exert cancer prevention effects by affecting classical signaling pathways, immune checkpoints, and gut microbiome. We also introduce novel cancer chemoprevention strategies and summarize the role of natural compounds in improving chemotherapy regimens. Furthermore, we describe strategies for discovering anticancer compounds with low abundance and high activity, revealing the broad prospects of natural compounds in drug discovery for cancer chemoprevention. Moreover, we associate cancer chemoprevention with precision medicine, and discuss the challenges encountered in cancer chemoprevention. Finally, we emphasize the transformative potential of natural compounds in advancing the field of cancer chemoprevention and their ability to introduce more effective and less toxic preventive options for oncology.

Despite the rapid evolution of targeted and immunotherapies for hepatocellular carcinoma (HCC), a systematic comparison of their adverse event profiles remains limited. This review addresses this critical gap by synthesizing data from 13 randomized controlled trials (RCTs) to prioritize treatment regimens on the basis of safety, thereby guiding clinical decision-making in an era of expanding therapeutic options.

Clinical studies focusing on targeted and immunotherapies in HCC patients were chosen from databases such as PubMed, Embase, Web of Science and the Cochrane Library, which spans from 2008 to 2023. Data processing and evaluation followed PRISMA guidelines, with a random-effects model employed to merge the data. Network models were then developed, with adverse events serving as the primary endpoint for analysis.

A comprehensive review of the relevant literature was conducted, identifying 13 randomized controlled trials (RCTs) encompassing 13 treatment protocols for HCC. This study included a total of 10,760 patients. Adverse events within the same category were initially consolidated, followed by the sequential construction of a network model to assess the risk probabilities associated with different targeted immunotherapy regimens for various adverse events and establish priority rankings.

Cabozantinib, camrelizumab, and their combination therapy for HCC are associated with a higher incidence of common adverse reactions, whereas durvalumab, lenvatinib, and their combination therapy are less likely to cause common adverse effects.

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.

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. While early-stage HCC can be effectively managed with surgical resection and other interventions, treatment options for advanced HCC are limited. Current systemic treatments for advanced HCC include VEGF-targeted tyrosine kinase inhibitors (Sorafenib, Lenvatinib), and the combination therapy of anti PD-1/PD-L1 and anti VEGF (Atezolizumab plus Bevacizumab, Camrelizumab plus Rivoceranib). However, the lack of response to these drugs and the emergence of acquired drug resistance significantly impairs their efficacy. Numerous studies have demonstrated that the tumor immune microenvironment (TIME) plays a crucial role in modulating the response to these therapies. Various immune cells and their secreted factors within the TIME play a pivotal role in the emergence of secondary drug resistance in HCC. This article reviews the mechanism of TIME promoting drug resistance, discusses the influence of current systemic HCC treatment drugs on TIME, and evaluates how these TIME changes affect the efficacy of treatment. A deeper understanding of the interaction between TIME and systemic treatment drugs may be beneficial to enhance the treatment effect, mitigate drug resistance of advanced HCC, and ultimately improve the prognosis of patients.

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 a major global health challenge, with over 50% of patients ineligible for curative treatments at diagnosis. The combination of molecular targeted therapies and immunotherapy has shown promise in improving outcomes for advanced HCC.

This meta-analysis aims to assess the efficacy of combining transarterial chemoembolisation (TACE) with immune-targeted therapies in patients with unresectable HCC.

A systematic review and meta-analysis conforming to PRISMA guidelines were conducted by searching PubMed, Embase, Web of Science, and the Cochrane Library for studies published up to January 5, 2025. Due to the limited clinical evidence, our study exclusively included retrospective studies based on propensity score matching (PSM) analysis that compared the efficacy of TACE in combination with immune-targeted therapy to immune-targeted therapy alone. Key outcomes assessed included objective response rate (ORR), disease control rate (DCR), one-year overall survival (1-OS), one-year progression-free survival (1-PFS), median overall survival (mOS), and median progression-free survival (mPFS).

A total of 9 PSM studies involving 2119 patients were included. The meta-analysis revealed that TACE significantly improved ORR, DCR, 1-OS, and 1-PFS, in addition to extending mOS and mPFS.

The findings suggest that the inclusion of TACE in treatment regimens for unresectable HCC notably enhances tumour control and patient survival. This study provides moderate to high-quality evidence supporting the integration of TACE in advanced HCC management, particularly for those patients not meeting standard TACE criteria.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD 42025631817.

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.

Tumour-associated macrophages (TAMs) contribute to hepatocellular carcinoma (HCC) progression. However, while the pro-tumour and immunosuppressive roles of lipid-loaded macrophages are well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear.

Single-cell RNA sequencing was performed on mouse and human HCC tumour samples to elucidate the landscape of HCC TAMs. Macrophages were stimulated with various long-chain unsaturated fatty acids (UFAs) to assess immunosuppressive molecule expression in vitro. Additionally, in vivo and in vitro studies were conducted using mice with macrophage-specific deficiencies in fatty acid-binding protein 5 (FABP5) or peroxisome proliferator-activated receptor γ (PPARγ).

Single-cell RNA sequencing identified a subpopulation of FABP5+ lipid-loaded TAMs characterized by enhanced immune checkpoint blocker ligands and immunosuppressive molecules in an oncogene-mutant HCC mouse model and human HCC tumours. Mechanistically, long-chain UFAs released by tumour cells activate PPARγ via FABP5, resulting in immunosuppressive properties in TAMs. FABP5 deficiency in macrophages decreases immunosuppressive molecule expression, enhances T cell-dependent antitumour immunity, diminishes HCC growth, and improves immunotherapy efficacy.

This study demonstrates that UFAs promote tumourigenesis by enhancing the immunosuppressive tumour microenvironment via FABP5-PPARγ signalling and provides a proof-of-concept for targeting this pathway to improve the efficacy of tumour immunotherapy.

Despite the role of tumour-associated macrophages (TAMs) in promoting tumour progression being well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear. Our study reveals that FABP5-mediated unsaturated fatty acid metabolism in TAMs is crucial for modulating antitumour T-cell immunity and influencing the efficacy of immunotherapy. This finding provides novel insights into the immunomodulatory roles of FABP5+ lipid-loaded TAMs in hepatocellular carcinoma and suggests that targeting FABP5 could offer a new approach to liver cancer treatment.

Locoregional therapies play a fundamental role in the treatment of patients with early and intermediate and locally advanced hepatocellular carcinomas. With encouraging recent advances in immunotherapy-based systemic therapies, locoregional therapies are being both promoted and challenged by new systemic therapy options. Combined locoregional and systemic therapies might enhance treatment outcomes compared with either option alone. This Series paper summarises the existing data on locoregional and systemic therapies for hepatocellular carcinoma, and discusses evidence from studies investigating their combination with a focus on their synergistic efficacy and safety.

The impact of low-level viremia(LLV) on the efficacy of immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma(uHCC) patients remains unclear. This study aims to investigate the effect of LLV on the outcomes of ICIs-based therapy in patients with uHCC.

In this multicenter retrospective study, we included patients with uHCC who received ICIs-based therapy at four centres between January 2019 and December 2022. All patients were positive for HBsAg and were on nucleos(t)ide analogues (NAs) antiviral therapy. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to balance baseline characteristics between the LLV and maintained virological response (MVR) groups. Proteomic analysis was performed on a subset of patients to identify differential protein expression.

A total of 329 patients (mean age 56 years; 92.4% male; 70.8% BCLC stage C) were included, with 170 patients in the LLV group and 159 in the MVR group. The objective response rate (ORR) was significantly lower in the LLV group compared to the MVR group (21.2% vs. 36.5%, p = 0.002), as was the disease control rate (DCR) (78.8% vs. 92.5%, p < 0.001). Median progression-free survival (mPFS) was shorter in the LLV group (7.6 vs. 12.6 months, p < 0.001), as was median overall survival (mOS) (22.8 vs. 40.0 months, p < 0.001). These differences remained consistent after PSM and IPTW adjustments. Multivariate analysis identified LLV as the only independent risk factor for overall survival (hazard ratio [HR] 0.522, 95% CI 0.348-0.781; p = 0.002). Proteomic analysis revealed significant differences in the expression of Flt3L, SLAMF1 and FGF-5 proteins between the LLV and MVR groups.

LLV is associated with poorer responses to ICIs-based therapy and reduced survival in patients with HBV-related uHCC.

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.

Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) pose a significant threat to human health worldwide, characterized by intricate pathogenesis. A PC-esterase domain containing 1A (PCED1A) is a critical number of the GDSL/SGNH superfamily.

The aim of this study is to explore the diagnostic value of PCED1A in HCC and CRC and its relationship with immune infiltration.

The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database, the Cancer Cell Line Encyclopedia database (CCLE), and the Human Protein Atlas (HPA) were used to detect the expression of PCED1A in tissues and cells. Cibersoft, Timer, and Xcell were used to analyze the effect of PCED1A on immune cell infiltration. The relationship between PCED1A and the immune checkpoint was analyzed. The coexpression analysis of PCED1A was conducted using the LinkedOmics database.

PCED1A was increased in HCC and CRC with poor prognosis. Immunohistochemistry demonstrated that PCED1A was highly expressed in HCC and CRC compared to corresponding normal tissues. PCED1A expression was related to poor overall survival (OS) and progression-free survival (PFS). High PCED1A expression was strongly associated with M2 macrophages, impacting HCC progression. Conversely, low PCED1A expression was closely related to Th2 cells in CRC. In addition, the checkpoint named PDCD1 showed a good correlation with PCED1A high expression group in HCC and CRC. Lastly, the PCED1A and ZNF family showed a complex and intertwined relationship through coexpression analysis on the LinkedOmics database.

PCED1A, related to tumor immune infiltration, is a promising diagnostic biomarker and a valuable therapeutic target for HCC and CRC.

Hepatocellular carcinoma (HCC) is one of the common malignant cancers worldwide. Although immunotherapy has improved the treatment outcome in HCC, a significant percentage of patients with advanced HCC still cannot benefit from immunotherapy. Therefore, developing new targets or combination therapeutic strategies to improve the efficacy of immunotherapy is urgently needed. A deeper understanding of the mechanisms underlying immune regulation may help in this regard. The tumor microenvironment (TME) consists of a diverse set of components modulating the efficacy of immunotherapy. Cancer-associated fibroblasts (CAFs) are critical components of the TME and can regulate both tumor and immune cells through secreted cytokines and exosomes that impact various signaling pathways in target cells. CAF-derived cytokines can also participate in extracellular matrix (ECM) remodeling, thereby impacting cancer progression and tumor responsiveness to immunotherapy among other effects. A thorough understanding of the phenotypic and functional profile dynamism of CAFs may lead the way for new treatment strategies and/or better treatment outcomes in HCC patients. In this review, we outline the biomarkers and functional heterogeneity of CAFs in HCC and elaborate on molecular mechanisms of CAFs, including anti-programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) immunotherapy. We also examine current clinical implications of CAFs-related targets as potential therapeutic candidates in HCC.

In recent years, several global phase III trials have shown that combinations of immune checkpoint inhibitors (ICIs) offer superior efficacy and survival compared to multi-kinase inhibitors, establishing them as the gold standard for treating patients with advanced hepatocellular carcinoma (HCC). This success has led to investigations into expanding the use of immunotherapy into various other settings and populations, including neoadjuvant and adjuvant therapies, patients with decompensated liver function and those awaiting liver transplantation. Despite its proven efficacy, a significant number of patients still develop resistance to immunotherapy, highlighting the need for innovative strategies to address this challenge. Approaches aimed at enhancing tumour immunogenicity, such as combining immunotherapy with transarterial chemoembolization or radiation therapies, show significant promise. Additionally, novel immunotherapeutics - such as triplet therapy, bispecific antibodies, adoptive T-cell therapy and cancer vaccines - are in early development for HCC. These agents have demonstrated potential for synergistic effects with existing ICIs, with initial studies yielding positive outcomes. In this review, we offer our future perspective on immunotherapy, emphasizing emerging indications, novel combination strategies and the development of new immunotherapeutic agents. Overall, the future of immunotherapy in HCC is brimming with extraordinary potential, set to transform the treatment landscape and redefine the possibilities for managing this challenging disease.

The use of immune checkpoint inhibitors (ICIs) in treating hepatocellular carcinoma (HCC) has grown significantly. However, the therapeutic benefits of ICIs alone are notably modest. This meta-analysis assesses the efficacy and safety of using PD-1/PD-L1 inhibitors in conjunction with tyrosine kinase inhibitors (TKIs) for patients with advanced or unresectable HCC.

An extensive search of the literature was performed using databases such as PubMed, Web of Science, Embase, and the Cochrane Library, capturing randomized controlled trials (RCTs) until 16 October 2024. Efficacy was measured by progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Safety was gauged through the occurrence of treatment-related adverse events (TRAEs). Hazard ratios (HRs) for PFS and OS, along with risk ratios (RRs) for ORR, DCR, and TRAEs, were calculated, each with 95% confidence intervals (CIs). Heterogeneity among studies was quantified using Cochran's Q test, I2 statistics, and 95% prediction intervals (PIs).

This analysis incorporated 4 studies with a total of 2,174 patients. Treatment regimens combining PD-1/PD-L1 inhibitors with TKIs significantly improved PFS (HR = 0.694, 95% CI: 0.527-0.914; 95% PI: 0.228-2.114) and ORR (RR = 2.303, 95% CI: 1.360-3.902; 95% PI: 0.408-12.991) compared with first-line monotherapy or TKI monotherapy in the overall population. Subgroup analysis indicated that the improvements in PFS and OS were particularly significant among patients of Asian descent or those with hepatitis B virus (HBV) infection (all p < 0.05). While the occurrence of any grade TRAEs did not differ significantly between the two groups (RR = 1.016, 95% CI: 0.996-1.036; 95% PI: 0.941-1.097), the incidence of serious (RR = 2.068, 95% CI: 1.328-3.222; 95% PI: 0.487-8.776) and grade ≥3 TRAEs (RR = 1.287, 95% CI: 1.020-1.624; 95% PI: 0.574-2.883) increased in patients treated with the combination of PD-1/PD-L1 inhibitors and TKIs.

This study revealed that combining PD-1/PD-L1 inhibitors with TKIs in the treatment of advanced or unresectable HCC leads to superior clinical outcomes compared to first-line monotherapy or TKIs alone, particularly in patients with HBV infection and those of Asian descent. Clinicians are advised to be vigilant regarding the potential for TRAEs in clinical settings.

Recent advances in the systemic treatment of advanced hepatocellular carcinoma (HCC) with immunotherapy have once again reignited discussion over the role of combined therapy in earlier stages. This year, different international meetings have presented recent results from clinical trials on adjuvant therapy alone (IMBrave-050) and combined with transarterial chemoembolization (EMERALD-1 and LEAP-12). Increased enthusiasm for the use of adjuvant and neoadjuvant therapy for liver transplantation, surgery, and local-regional treatment of HCC has been shown. However, the initial results from these trials should be interpreted cautiously as we wait for final analyses and effects on overall survival. In this position paper from the special interest group from the Latin American Association for the Study of Liver Diseases (ALEH), we underline the caveats of the applicability of these potential treatments in our region, explore points of agreement, and highlight areas of uncertainty. Moreover, we underscore the role of hepatologists in the clinical decision-making process and management of these patients.

Immunotherapy has improved survival in patients with advanced hepatocellular carcinoma (HCC); yet, objective radiological responses occur in only about 20% of cases, suggesting variable benefits. This study aimed to identify serologic markers predictive of response to immune checkpoint inhibitors (ICIs). A cohort of 38 advanced HCC patients receiving immunotherapy was prospectively analyzed. Levels of cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and cytokines were measured pre-treatment and three months post-treatment initiation. Genomic profiling of ctDNA was also conducted. Baseline levels of cfDNA and ctDNA effectively discriminated HCC patients based on their radiological response to ICIs. Additionally, individuals with pathologic mutations in the CDKN2A gene exhibited significantly reduced survival. Patients with progressive disease (PD) as their best radiological response had significantly fewer copy number variations (CNVs) than those with a radiological response. Furthermore, levels of IL10, PD1, and TGFβ assessed after three months of treatment showed significant variations correlating with survival status. In conclusion, the analysis of cfDNA, ctDNA, and cytokines may improve treatment selection for HCC patients by predicting their expected response to immunotherapies.

Immune checkpoint inhibitors (ICIs) have revolutionized hepatocellular carcinoma (HCC) treatment, while immune-related adverse events (IRAEs) pose significant challenges. We report a 60-year-old male with unresectable HCC who developed Guillain-Barré syndrome (GBS), a rare but severe neurologic complication, after three cycles of sintilimab plus bevacizumab biosimilar and conventional transarterial chemoembolization (c-TACE). The patient presented with progressive ascending weakness, reaching symmetric quadriparesis with proximal muscle strength of 2/5 in upper limbs and 1/5 in lower limbs. Following sintilimab discontinuation, treatment with intravenous immunoglobulin (2 g/kg) and oral prednisone (30 mg/day) achieved complete neurological recovery within one month. Given the patient's favorable initial tumor response and strong request, immunotherapy was cautiously reinstated using tislelizumab after thorough clinical evaluation. Following four cycles of treatment, significant tumor response enabled successful conversion surgery with major pathological response (necrosis rate >70%). With 26-month survival and no evidence of recurrence, this case demonstrates the potential feasibility of ICI rechallenge with an alternative PD-1 inhibitor following sintilimab-induced GBS. Our experience suggests that ICI-related neurological adverse events may be drug-specific rather than class-specific, potentially providing valuable treatment options for patients showing favorable tumor response despite experiencing severe IRAEs, though larger studies are needed for validation.

Hepatocellular carcinoma remains a life-threatening malignancy with limited therapeutic options following the failure of second-line treatments1,2. Oncolytic viruses selectively replicate in and lyse cancer cells, releasing neoantigens and stimulating systemic antitumour immunity3, offering a potential therapeutic option. Here we present the results of a multicentre phase 1 clinical trial evaluating VG161, an engineered oncolytic herpes simplex virus that expresses IL-12, IL-15, IL-15Rα and a PD-1-PD-L1-blocking fusion protein4, for safety and efficacy in patients with advanced liver cancer. VG161 was well tolerated, with no dose-limiting toxicities observed, and it demonstrated promising efficacy by reshaping the tumour immune microenvironment and re-sensitizing tumours that were previously resistant to systemic treatments. Notably, we also found that patients who had previously been sensitive to checkpoint inhibitor therapy showed enhanced efficacy with VG161 treatment. Furthermore, we developed an efficacy-prediction model based on differentially expressed genes, which successfully identified patients who were likely to benefit from VG161 and predicted prolonged overall survival. These findings position VG161 as a promising third-line therapeutic option for refractory hepatocellular carcinoma. This provides a new avenue for treatment and advances the field of oncolytic virus-based immunotherapies. ClinicalTrials.gov registration: NCT04806464 .

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with chronic infections by hepatotropic viruses such as hepatitis B virus (HBV), and hepatitis C virus (HCV), being major risk factors. Chronic infections with these viruses are the leading cause of HCC worldwide, with HBV alone responsible for over 50% of cases. Despite advances in direct-acting antivirals (DAAs) for HCV and nucleos(t)ide analogues (NAs) for HBV, challenges remain in HCC prevention, early detection, and treatment. Recent research highlights the role of viral-induced metabolic alterations, such as the Warburg effect, mitochondrial dysfunction, and lipid dysregulation, in promoting HCC. Moreover, immune checkpoint inhibitors have emerged as effective treatments for advanced HCC, though responses vary between HBV- and HCV-related cancers. Additionally, novel therapeutic approaches and metabolic-targeted therapies offer promising avenues for virus-associated HCC treatment. Advancements in liquid biopsy biomarkers and artificial intelligence-driven diagnostics are improving HCC surveillance and risk stratification, potentially enabling earlier interventions. While HBV vaccination has significantly reduced HCC incidence, disparities in global vaccination coverage persist. Furthermore, antiviral therapies combined with structured surveillance programs have proven effective in reducing HCC incidence and mortality. This review highlights the complex connection between viral, genetic, and environmental factors in HCC development and underscores the importance of integrated prevention strategies to reduce its burden globally.

There is still no noninvasive, automated, and accurate model for guiding physicians in the decision-making of transarterial chemoembolization combined with microwave ablation (TACE-MWA) in intermediate-stage hepatocellular carcinoma (HCC).

To develop a prognostic score based on the tumor burden and radiomic features for the prediction of the long-term survival of patients with intermediate-stage HCC after TACE-MWA.

From June 2008 to October 2022, a total of 2189 consecutive patients from seven tertiary-care hospitals with intermediate-stage HCC who received initial TACE combined with MWA were enrolled. Among them, 2189 were divided into training cohort (N = 1753), and internal test cohort (N = 436) in a single center, and 316 patients were assigned to external test cohort in another 6 centers. A prognostic scoring system was constructed using tumor burden and radiologic features (TBR) and compared with conventional predicting systems.

In training cohort, multivariate Cox regression analysis suggested that tumor burden (hazard ratio (HR), 0.693; 95% confidence interval (CI): 0.505, 0.814; 1 point per 1.0 increase, p = 0.024), radiologic features (HR, 0.349; 95% CI: 0.236, 0.517; p < 0.001), and alpha-fetoprotein (HR, 1.629; 95% CI: 1.280, 2.073; p < 0.001) were independent prognostic factors for OS. A prognostic model that comprises TBR was built, which showed significantly higher AUC values than other clinical stagings in all three cohorts. Moreover, the TBR score provided greater net benefit across the range of reasonable threshold probabilities than other models. Based on cutoff values of 32 and 74 centiles of the TBR score, the cohort was divided into low-, middle-, and high-risk strata, which provide consistent performance in survival discrimination across different patient subgroups.

The TBR score serves as an efficient instrument for risk stratification, guiding the course of adjuvant targeted and immunotherapies for HCC patients undergoing TACE-MWA combined treatment.

A retrospective, multi-institutional study.

The combination of immune checkpoint inhibitors targeting anti-programmed cell death-1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) with antiangiogenic agents has emerged as a revolutionary therapy for advanced hepatocellular carcinoma (aHCC). Key antiangiogenic medications encompass monoclonal antibodies targeting vascular endothelial growth factor (anti-VEGF mAbs) and multiple kinase inhibitors (MKIs). The aim of this study is to assess the difference of efficacy and safety between 2 combination therapies. This study retrospectively examined the outcomes of 57 patients with aHCC who underwent first-line treatment with a combination of immune checkpoint inhibitors and antiangiogenic therapy at the First Affiliated Hospital of Anhui Medical University, from September 2018 to July 2023. The analysis, conducted using SPSS software, focused on patient outcomes such as tumor response (assessed according to modified Response Evaluation Criteria in Solid Tumors criteria), objective response rate, disease control rate, progression-free survival, overall survival, and safety. Comparisons among different groups were also made. The anti-PD-1/anti-PD-L1-anti-VEGF mAbs group showed a trend of higher partial response rate (37.50% vs 22.45%), objective response rate (37.50% vs 24.49%), disease control rate (62.50% vs 59.18%), and seemed to achieve longer median progression-free survival (14.93 vs 14.90 months) and median overall survival (15.80 vs 11.10 months) without higher grade 3 or higher adverse events comparing to anti-PD-1/anti-PD-L1-MKIs group. Subgroup analysis showed that the anti-PD-1-lenvatinib group achieved longer median progression-free survival (23.97 months), while the anti-PD-1-regorafenib group achieved longer median overall survival (37.97 months). The anti-PD-1/anti-PD-L1 combined with anti-VEGF mAbs was effective and tolerable compared to anti-PD-1/anti-PD-L1-MKIs in aHCC. The addition of lenvatinib or regorafenib may provide promising incremental benefit for patients with aHCC.

Systemic treatment for unresectable hepatocellular carcinoma (HCC) has rapidly advanced, with immune checkpoint inhibitors now the preferred first-line option. However, with multiple agents available and no established treatment sequence, selecting the most suitable second-line (2L) therapy remains challenging. While sorafenib is frequently chosen for 2L treatment, comprehensive data supporting its use is limited. This study evaluates the effectiveness of sorafenib as 2L therapy and factors influencing outcomes following first-line treatment failure in advanced HCC patients.

This is a retrospective, multicenter study, including 81 patients with unresectable HCC from 12 European centers who received sorafenib as 2L treatment. Median overall survival (mOS), median progression-free survival (mPFS), radiological response to treatment, and toxicity were evaluated. Univariable and multivariable analyses were performed to identify potential predictors of clinical benefit.

In this cohort, some patients were treated with 2L sorafenib mOS for 7.4 months (95% CI: 6.6-13.6) and other patients were treated with mPFS for 3.7 months (95% CI: 3.0-4.8). Multivariable analysis revealed the best median OS for patients with CP A and AFP levels < 400 ng/mL (15.5 months). Adverse events (AE) of grade ≥ 3 were reported in 59.4% of patients.

In this real-world cohort of European patients with unresectable HCC, the outcome of sorafenib treatment in the 2L setting was comparable to that of the other established 2L treatment options in patients with preserved liver function and good performance status. This study contributes to the understanding of the role of sorafenib in the 2L setting and underscores the need for further research to identify predictive factors for response and survival in order to optimize treatment algorithms for advanced HCC.

This study aimed to develop and evaluate the value of a nomogram based on quantitative MR signal intensity to predict response to combined systemic therapy of anti-angiogenesis and immune checkpoint inhibitor (ICI) in hepatocellular carcinoma (HCC) patients.

117 HCC patients who underwent the combined systemic treatment at a tertiary hospital between September 2020 and May 2024 were enrolled and divided into a development cohort (n = 82) and a validation cohort (n = 35). The predictive value of the relative signal intensity attenuation index (rSIAI) based on enhanced MR parameters and laboratory parameters on disease control was evaluated using receiver operating characteristic (ROC) curves, with the determination of optimal cut-off values (COVs) accomplished via Youden's index. Univariate and multivariable analyses were conducted to evaluate the association between COVs and disease control. The validity of the COVs was further confirmed through chi-square testing and calculation of Cramer's V coefficient (V). A nomogram was constructed based on the multivariable logistic regression model and evaluated for clinical applicability.

rSIAI from arterial to portal phase (rSI_ap) in combination with peripheral T-cell subset (CD4+) achieved the most accurate predictive performance for outcome compared to rSI_ap or CD4+ alone, with an area under the curve (AUC) of the ROC of 0.845 (95% CI, 0.748-0.915). A nomogram based on rSI_ap and CD4+ was constructed. Calibration and decision curve analyses confirmed the clinical relevance and value of the nomogram.

The nomogram based on rSI_ap has the potential to be a non-invasive tool for predicting disease control in advanced HCC patients who have received combined anti-angiogenesis and ICI therapies.

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.

Aberrant expression of programmed death ligand-1 (PD-L1) facilitates tumor immune evasion. Protein arginine methyltransferase 3 (PRMT3), a member of type I PRMT family, mediates asymmetric dimethylarginine (ADMA) modification of various substrate proteins. This study investigates the role of PRMT3 in PD-L1-associated tumor immunosuppression in hepatocellular carcinoma (HCC). Hepatocyte-specific knockout of Prmt3 significantly suppressed HCC progression in DEN-CCL4-treated mice. Knockout of Prmt3 in HCC cells markedly increased CD8+ T cell infiltration, and reduced lactate production in tumors. PRMT3 interacted with pyruvate dehydrogenase kinase 1 (PDHK1), asymmetric dimethylation of PDHK1 at arginine 363 and 368 residues and increased its kinase activity. The R363/368 K mutant or inhibition of PDHK1 by JX06 blocked the effect of PRMT3 on lactate production. JX06 treatment also attenuated the tumor-promoting role of PRMT3 in HCC in vitro and in vivo. Furthermore, RNA-seq analysis revealed that knockout of PRMT3 downregulates the tumor-associated immune checkpoint, PD-L1, in tumor tissues. Chromatin immunoprecipitation (ChIP) assay demonstrated that PRMT3 promotes lactate-induced PD-L1 expression by enhancing the direct binding of histone H3 lysine 18 lactylation (H3K18la) to the PD-L1 promoter. Tissue microarray analysis showed a positive correlation between PRMT3 and PD-L1 expression in HCC patients. Anti-PD-L1 treatment reversed PRMT3-induced tumor growth and restored CD8+ T cell infiltration. Our research links PRMT3-mediated metabolic reprogramming and immune evasion, revealing that the PRMT3-PDHK1-lactate-PD-L1 axis may be a potential target for improving the efficacy of immunotherapy in HCC.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. HCC treatment is challenging; surgical resection is the primary curative treatment for early-stage disease, but recurrence rates are high. Immune checkpoint inhibitors (ICIs) are a promising neoadjuvant treatment that can reduce recurrence rates and mortality after surgery and achieve complete/partial responses. Clinical trials provide strong evidence for the efficacy and safety of ICI monotherapy for neoadjuvant HCC treatment.

Hepatocellular carcinoma is a leading and increasing contributor to cancer-related death worldwide. Recent advancements in both liver-directed therapies in the form of yttrium-90 (90Y) radioembolization (RE) and systemic therapy in the form of immune checkpoint inhibitors (ICI) have expanded treatment options for patients with an otherwise poor prognosis. Despite these gains, ICIs and 90Y-RE each have key limitations with low objective response rates and persistent hazard of out-of-field recurrence, respectively, and overall survival remains low. However, each therapy's strength may mitigate the other's weakness, making them potentially ideal partners for combination treatment strategies. This review discusses the scientific and clinical rationale for combining 90Y-RE with ICIs, highlights early clinical trial data on its safety and effectiveness, and proposes key issues to be addressed in this emerging field. With optimal strategies, combination therapies can potentially result in increasing likelihood of durable and curative outcomes in later stage patients.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with an estimated 750,000 deaths in 2022. Recent emergence of molecular targeted agents and immune checkpoint inhibitors and their combination therapies have been transforming HCC care, but their prognostic impact in advanced-stage disease remains unsatisfactory. In addition, their application to early-stage disease is still an unmet need. Omics profiling studies have elucidated recurrent and heterogeneously present molecular aberrations involved in pro-cancer tumor (immune) microenvironment that may guide therapeutic strategies. Recurrent aberrations such somatic mutations in TERT promoter and TP53 have been regarded undruggable, but recent studies have suggested that these may serve as new classes of therapeutic targets. HCC markers such as alpha-fetoprotein, glypican-3, and epithelial cell adhesion molecule have also been explored as therapeutic targets. These molecular features may be utilized as biomarkers to guide the application of new approaches as companion biomarkers to maximize therapeutic benefits in patients who are likely to benefit from the therapies, while minimizing unnecessary harm in patients who will not respond. The explosive number of new agents in the pipelines have posed challenges in their clinical testing. Novel clinical trial designs guided by predictive biomarkers have been proposed to enable their efficient and cost-effective evaluation. These new developments collectively facilitate clinical translation of personalized molecular-targeted therapies in HCC and substantially improve prognosis of HCC patients.