The integration of chemotherapy and phototherapy for treating advanced liver cancer has gained considerable attention. However, challenges such as short drug retention times significantly impact patient prognosis. We introduce a light-triggered nanosystem that employs molecular aggregation control for PTT and sustained chemotherapy. This nanosystem, known as Reg/IR783@CM nanoparticles (RIMNPs), consists of a core-shell carrier-free nanodrug self-assembled from the chemotherapy drug regorafenib (Reg) and the photothermal agent IR783, coated with a homologous liver cancer cell membrane. The developed core-shell nanocarrier exhibits excellent water dispersibility, high drug load, extended blood circulation, and tumor site enrichment. Upon light exposure, the nanosystem provides outstanding near-infrared imaging and robust photothermal effects. Concurrently, light exposure accelerates the degradation of the outer IR783 layer, resulting in regorafenib exposure and triggering secondary assembly, which significantly enhances drug retention at the tumor site. Our findings indicate that the nanosystem effectively suppresses tumor growth by combining photothermal therapy with the inhibition of tumor cell proliferation and angiogenesis, and by modulating tumor-associated macrophages. Notably, this nanosystem also demonstrates low cytotoxicity and high biocompatibility. This study presents a novel light-driven in-situ assembly strategy, offering a simplified and effective approach for constructing tumor imaging and treatment systems.

Hepatocellular carcinoma (HCC) is a global health concern because of its rising prevalence and high fatality rates. Conventional treatments for advanced HCC (aHCC) have limited success, emphasizing the need for novel treatment options. Radiotherapy (RT) treatments, such as stereotactic body radiation and proton therapy, improve local tumor management via precision targeting. Moreover, immune checkpoint inhibitors (ICIs) that target the programmed cell death protein 1(PD-1)/PD ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) pathways have promise for systemic antitumor effectiveness. The combination of RT and ICIs takes advantage of their complementary mechanisms: RT kills immunogenic cells and controls the tumor microenvironment to increase antigen presentation, whereas ICIs enhance and maintain antitumor immune responses. This combination enhances tumor regression and immune response in aHCC, improving response rate and progression-free survival with manageable safety. The present review aimed to summarize the rationale for combining RT + ICIs in patients with aHCC and clinical outcomes, as well as ways to enhance this combination technique. The combination of these models is a promising technique for improving outcomes for patients with aHCC and warrants further investigation.

The aim of this study was to assess the prognostic value of the multi-PDZ domain protein (MPDZ) in hepatocellular carcinoma (HCC). MPDZ expression in HCC and normal liver tissue samples were analyzed using TCGA-LIHC data and validated in the GSE14520, GSE62232, GSE76427, GSE121248, and GSE136247 datasets. MPDZ's prognostic value in HCC was evaluated based on Kaplan-Meier survival analysis and Cox proportional risk models. The correlation of MPDZ with other prognostic factors was explored by combined survival analysis and stratified survival analysis. The differentially expressed genes between patient groups stratified on the basis of MPDZ levels in TCGA-LIHC were screened using R and functionally annotated by the GO and KEGG pathway analysis by DAVID. Furthermore, gene set enrichment analysis was conducted to determine the basic molecular mechanism of MPDZ in HCC, and the protein-protein interactions, gene-gene interactions, and immune infiltration status of MPDZ was analyzed by STRING, GeneMania, and TIMER. Our findings indicate that MPDZ is downregulated in HCC and portends worse prognosis. Bioinformatics analysis revealed a strong link between MPDZ and liver cancer progression, liver cancer survival, multiple metabolic pathways, and multiple signaling pathways. In addition, our findings indicate that MPDZ expression is associated with several key genes in the ferroptosis pathway and m6A methylation. Finally, immunohistochemical assessment of clinical specimens confirmed low MPDZ protein expression in HCC tissues relative to paraneoplastic tissues. Taken together, MPDZ is a promising biomarker for the diagnosis and prognosis of HCC.

The asialoglycoprotein receptor (ASGPR) is specifically expressed in hepatocytes. Sugar molecules, such as asialoglycoprotein, galactose, galactosamine, and N-acetyl galactosamine (GalNAc), have a high affinity for ASGPR. This review summarizes the structure of ASGPR, the distribution of this molecule in different cells, and the factors influencing the binding of GalNAc to ASGPR. We introduce the application of GalNAc in targeted delivery into hepatocytes by forming conjugated compounds with RNAs and small molecules, and the standard methods for synthesizing GalNAc are also briefly presented. This is to provide an overview of the current research on GalNAc and to shed light on the design of the new GalNAc.

Cancer treatments such as surgery and chemotherapy have several limitations, including ineffectiveness against large or persistent tumors, high relapse rates, drug toxicity, and non-specificity of therapy. Researchers are exploring advanced strategies for treating this life-threatening disease to address these challenges. One promising approach is targeted drug delivery using prodrugs or surface modification with receptor-specific moieties for active or passive targeting. While various drug delivery systems have shown potential for reaching hepatic cells, nano-carriers offer significant size, distribution, and targetability advantages. Engineered nanocarriers can be customized to achieve effective and safe targeting of tumors by manipulating physical characteristics such as particle size or attaching receptor-specific ligands. This method is particularly advantageous in treating liver cancer by targeting specific hepatocyte receptors and enzymatic pathways for both passive and active therapeutic strategies. It highlights the epidemiology of liver cancer and provides an in-depth analysis of the various targeting approaches, including prodrugs, liposomes, magneto-liposomes, micelles, glycol-dendrimers, magnetic nanoparticles, chylomicron-based emulsion, and quantum dots surface modification with receptor-specific moieties. The insights from this review can be immensely significant for preclinical and clinical researchers working towards developing effective treatments for liver cancer. By utilizing these novel strategies, we can overcome the limitations of conventional therapies and offer better outcomes for liver cancer patients.

Combination of multiple therapies is a common approach to treating patients with unresectable hepatocellular carcinoma (uHCC). The impact of immune checkpoint inhibitors (ICIs) on prognosis in uHCC patients treated with transarterial chemoembolization (TACE) and lenvatinib remains unclear.

The purpose of this study was to compare the efficacy and safety of TACE plus lenvatinib plus ICIs (TACE+L+I) with TACE plus lenvatinib (TACE+L) in the treatment of patients with uHCC.

Publicly available studies comparing the efficacy and safety of TACE+L+I and TACE+L in the treatment of uHCC were collected from the databases PubMed, Embase and Cochrane Library, with a cut-off date of November 1, 2024. Stata SE 15 software was used for analysis.

Fifteen studies with a total of 1365 patients were included, 688 in the TACE+L+I group and 677 in the TACE+L group. Meta-analysis showed that the TACE+L+I group was significantly higher than the TACE+L group in complete response (RR = 2.34, 95%CI:1.53, 3.59, p < 0.0001), partial response (RR = 1.45, 95%CI:1.28, 1.64, p < 0.0001), objective response rate (RR = 1.55, 95%CI:1.39, 1.73, p < 0.00001), and disease control rate (RR = 1.22, 95%CI:1.10, 1.36, p = 0.0003). The TACE+L+I group was significantly lower than the TACE+L group in progression of disease (RR = 0.39, 95%CI:0.30, 0.51, p < 0.00001). Moreover, TACE+L+I group was not significantly different from TACE+L group in stable disease (RR = 0.85, 95%CI:0.69, 1.03, p = 0.10). The TACE+L+I group was significantly higher than the TACE+L group in overall survival (HR = 2.32, 95%CI:1.95, 3.15, p<0.05) and progression-free survival (HR = 2.30, 95%CI:1.80, 2.93, p<0.05). The TACE+L+I group had a significantly higher incidence of hypothyroidism compared to the TACE+L group (RR = 1.81, 95%CI:1.20, 2.71, p<0.05), but there was no significant difference in other adverse events, such as hypertension, diarrhea, hand-foot syndrome, fatigue, elevated AST, elevated ALT, decreased appetite, hypothyroidism, abdominal pain, thrombocytopenia, rash, and nausea.

ICIs significantly improved the survival outcome of uHCC treated with TACE+L, and increased the incidence of hypothyroidism. However, this conclusion still needs further validation in the future with more high-quality randomized controlled trials and longer follow-up.

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.

The efficacy of immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) is limited by heterogeneity in individual responses to therapy. The heterogeneous phenotypes and crucial roles of cancer-associated fibroblasts (CAFs) in immunotherapy resistance remain largely unclear.

A specific CAF subset was identified by integrating comprehensive single-cell RNA sequencing, spatial transcriptomics and transcriptome profiling of patients with HCC with different responses to antiprogrammed cell death protein 1 (anti-PD-1) therapy. Mouse orthotopic HCC models and a coculture system were constructed, and cytometry by time-of-flight analysis was performed to investigate the functions and mechanisms of specific CAFs in the immune context of HCC.

We identified a distinct flavin-containing monooxygenase 2 (FMO2)+ CAF subset associated with a favorable response to anti-PD-1 therapy and better clinical outcomes. FMO2+ CAFs increase anti-PD-1 treatment efficacy by promoting tertiary lymphoid structure formation and increasing the infiltration of CD8+ T cells and M1-like macrophages through the C-C motif chemokine ligand 19 (CCL19)-C-C motif chemokine receptor 7 axis. Mechanistically, FMO2 promotes nuclear factor kappa B/p65-mediated CCL19 expression by competitively binding to glycogen synthase 1 (GYS1) with praja ring finger ubiquitin ligase 1 (PJA1), thereby suppressing the PJA1-mediated proteasomal degradation of GYS1. CCL19 treatment potentiated the therapeutic efficacy of anti-PD-1 therapy in mouse orthotopic HCC models. A favorable immunotherapy response was observed in patients with HCC with high serum levels of CCL19.

We identified a novel FMO2+ CAF subset that serves as a critical regulator of microenvironmental immune properties and a predictive biomarker of the immunotherapy response in patients with HCC. CCL19 in combination with anti-PD-1 therapy may constitute a novel therapeutic strategy for HCC.

Hepatocellular carcinoma (HCC) is a malignant tumor characterized by rapid progression. To explore the regulatory mechanism of rapid tumor growth and metastasis, we conducted proteomic and scRNA-Seq analyses on advanced HCC tissues and identified a significant molecule, guanine monophosphate synthase (GMPS), closely associated with the immune evasion in HCC. We analyzed the immune microenvironment characteristics remodeled by GMPS using scRNA-Seq and found GMPS induced tumor immune evasion in HCC by impairing the tumor-killing function of CD8 + T cells. Further investigation revealed that GMPS increased PD-L1 expression by regulating its ubiquitination and glycosylation modification. Mechanistically, GMPS enhanced the bond between PD-L1 and the catalytic subunit STT3A of oligosaccharyltransferase (OST) by acting as an additional module connecting the Sec61 channel complex and STT3A, which aided in the translocation and modification of nascent peptides. Increased PD-L1 impaired the tumor-killing function of CD8 + T cells, leading to the immune evasion. Importantly, targeting GMPS with angustmycin A, an inhibitor of GMPS activity, significantly suppressed PD-L1 expression and tumor growth in HCC, which also increased the sensitivity to anti-CTLA-4 immunotherapy. These findings suggested the potential of targeting GMPS as a promising therapeutic approach for HCC.

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.

In a recently published 4-year overall survival (OS) update from the phase III clinical trial named HIMALAYA (NCT03298451), single tremelimumab plus regular interval durvalumab (a regimen termed STRIDE) demonstrated significantly improved OS compared with sorafenib in the first-line setting of unresectable hepatocellular carcinoma (uHCC). Although dual immunotherapy represents a novel treatment option for uHCC, the economic implications of these high-priced drugs require further exploration. This study aimed to evaluate the cost-effectiveness of STRIDE in uHCC to inform first-line treatment decisions and help allocate medical resources most effectively.

Using a partitioned survival model, we conducted a cost-effectiveness analysis comparing STRIDE to sorafenib in the first-line treatment of uHCC. Clinical information was gathered from the phase III HIMALAYA trial. Costs and health state utilities data were derived from previous literature. Uncertainty of the model was assessed through one-way sensitivity analysis and probabilistic sensitivity analysis.

Total costs, life years, quality-adjusted life years (QALYs), incremental QALYs and incremental cost-effectiveness ratio (ICER).

US payer perspective.

393 participants in the STRIDE group and 389 participants in the sorafenib group who were diagnosed with uHCC and had no previous systemic treatment.

Single-dose tremelimumab plus monthly durvalumab (STRIDE) versus sorafenib.

Treatment with STRIDE provided an additional 0.51 QALYs at an incremental total cost of United States dollar ($)9812. The ICER of STRIDE was $19 239 per QALY compared with sorafenib, which falls below the willingness-to-pay threshold of $150 000 per QALY. Sensitivity analyses indicated that our results were robust to the variation ranges of key inputs.

In this economic evaluation comparing two first-line systemic therapies for uHCC patients, STRIDE was cost-effective compared with sorafenib from a US payer perspective. Our study is the first to demonstrate that immunotherapy can provide both survival benefits and economic viability in uHCC.

Cancer-associated fibroblasts (CAFs) are key drivers of hepatocellular carcinoma (HCC) through their promotion of fibrosis and immune suppression activity. To overcome this stroma-immune barrier, we developed D/F@MRL, a stroma-immune co-targeting nanoplatform that enables the spatiotemporal coordination of CAF reprogramming and immune activation. In D/F@MRL, MMP-2-responsive hybrid liposomes (MRL) was employed to co-load digoxin (Dig) and PD-L1-degrading nanofibers (NFs). Upon encountering the MMP-2-enriched HCC stroma, D/F@MRL undergoes enzymatic cleavage, thereby enabling the targeted release of Dig and NFs within the HCC microenvironment. Mechanistically, Dig inhibits the phosphorylation of SMAD3 in CAFs, while PD-L1 degradation destabilizes the TGFβ receptor, synergistically silencing TGF-β/Smad signaling to reprogram CAFs. This combination not only disrupts the fibrotic barrier but also creates a feed-forward loop that further enhances drug penetration, while reinforcing the immune activation driven by Dig-induced immunogenic cell death (ICD) and PD-L1 degradation. In the humanized immune PDX model, D/F@MRL successfully reprogrammed CAFs and robustly remodeled the stromal and immune microenvironments without causing systemic toxicity, highlighting its promising potential for clinical translation. By integrating CAF reprogramming with ICD and immune checkpoint inhibition, this strategy overcame the limitations of single-target therapies, induced robust immune activation, further provided a clinic-transformative approach for fibrotic malignancies.

Neoantigen-based immunotherapy has emerged as a transformative approach in cancer treatment, offering precision medicine strategies that target tumor-specific antigens derived from genetic, transcriptomic, and proteomic alterations unique to cancer cells. These neoantigens serve as highly specific targets for personalized therapies, promising more effective and tailored treatments. The aim of this article is to explore the advances in neoantigen-based therapies, highlighting successful treatments such as vaccines, tumor-infiltrating lymphocyte (TIL) therapy, T-cell receptor-engineered T cells therapy (TCR-T), and chimeric antigen receptor T cells therapy (CAR-T), particularly in cancer types like glioblastoma (GBM). Advances in technologies such as next-generation sequencing, RNA-based platforms, and CRISPR gene editing have accelerated the identification and validation of neoantigens, moving them closer to clinical application. Despite promising results, challenges such as tumor heterogeneity, immune evasion, and resistance mechanisms persist. The integration of AI-driven tools and multi-omic data has refined neoantigen discovery, while combination therapies are being developed to address issues like immune suppression and scalability. Additionally, the article discusses the ongoing development of personalized immunotherapies targeting tumor mutations, emphasizing the need for continued collaboration between computational and experimental approaches. Ultimately, the integration of cutting-edge technologies in neoantigen research holds the potential to revolutionize cancer care, offering hope for more effective and targeted treatments.

This study aimed to investigate whether extracellular volume (ECV) fraction derived from equilibration contrast-enhanced computed tomography (CECT) affects prognosis in HCC patients receiving ICIs. This retrospective study ultimately included 211 HCC patients undergoing ICIs, of whom 60 were included in an internal validation to assess the reproducibility of the results. Baseline unenhanced and equilibrated CECT were used to measure CT values of the tumor, liver and aorta, which were combined with hematocrit to calculate the ECV fraction. Correlation analysis was used to investigate the association between tumor ECV and liver ECV fractions. The effects of clinical variables and ECV fraction on progression-free survival (PFS) and overall survival (OS) were evaluated using Cox proportional hazards models and Kaplan-Meier curves. Of these 151 patients, tumor ECV fraction positively correlated with liver ECV fraction. In the Lower tumor ECV group, PFS (5.6 vs. 7.6 months) and OS (10.5 vs. 15.5 months) were notably shorter than in the Higher tumor ECV group, while no significant differences were found between the Higher and Lower liver ECV groups. Furthermore, the multivariable Cox regression model demonstrated that higher tumor ECV fraction level was an independent protective factor for PFS and OS (all P < 0.001). Internal validation cohort preliminary demonstrated reproducibility of results. The tumor ECV fraction is expected to become a routine indicator before ICIs therapy for HCC patients in contrast to liver ECV fraction, contributing to their subsequent management.

Liver cancer is one of the major causes of cancer-related death in the world. As a breakthrough therapy, immunotherapy had significantly improved the prognosis of patients. However, the current research status and research hotspots in the field of liver cancer immunotherapy still lack systematic review. Based on the bibliometric analysis of highly cited papers, this study intended to reveal the current research status, research hotspots and future research trends in this field.

The purpose of this study was to analyze the national/regional contributions, authors and institutions cooperation network, keywords clustering and keywords burst analysis of highly cited papers on liver cancer immunotherapy through bibliometrics, so as to clarify the research frontier and development direction, and provide objective data support for future research direction and clinical practice.

The highly cited papers on liver cancer immunotherapy from the Web of Science core collection up to February 23, 2025 were retrieved, and 232 studies were included. CiteSpace was used to build a knowledge map, analyze the distribution of years, countries, authors, institutions and cooperation networks, and identify research hotspots and emerging trends through keyword clustering and burst detection.

The number of highly cited papers continued to increase from 2014 and reached a peak in 2022. China and the United States had the highest number of publications and the centrality of cooperation networks. The author with the highest number of papers was Llovet, Josep M, whose research direction mainly focused on immune checkpoint inhibitor combination therapy and molecular typing. The author with the highest cooperation network centrality was Duda, Dan G, whose research team focused on tumor microenvironment regulation. Harvard University and the University of Barcelona played an important central role in the institutional collaboration. Keywords analysis showed that immune checkpoint inhibitors, tumor microenvironment and combination therapy were the core of liver cancer immunotherapy. Burst keywords such as cell lung cancer, pembrolizumab, advanced melanoma, blockade, lymphocytes, etc. had revealed the research frontier of liver cancer immunotherapy research.

The research on liver cancer immunotherapy had made multi-dimensional progress, with China and the United States leading the global cooperation. The main research directions were the combination strategy of immunization, the regulation of tumor microenvironment and the exploration of novel targets. In the future, it is necessary to optimize treatment resistance solutions, integrate interdisciplinary resources, and promote the development of precision and personalized treatment.

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.

Irreversible electroporation (IRE) is a novel local tumor ablation technique that can potentially stimulate immune responses. However, IRE alone cannot effectively activate the immune system or prevent distant metastases. Therefore, this study utilized the biocompatibility of Chlorella vulgaris (C. vulgaris) and polydopamine (PDA) adhesive properties to encapsulate a PD-1 inhibitor (PI). The PDA coating protects the drug from degradation by stomach acid and enhances its intestinal absorption. This carrier demonstrates excellent in vivo drug release control and biodistribution, significantly increasing the oral bioavailability of PI. Combining IRE with this natural carrier significantly improves the therapeutic efficacy, which increases the local drug concentration and activates the immune system. This system demonstrates significantly improved therapeutic efficacy against local tumors compared with PI or IRE alone and significantly reduces PI-associated side effects. A convenient oral delivery system is developed using this readily available natural micro-carrier that not only improves the therapeutic effect of IRE but also mitigates its adverse effects, indicating significant potential for clinical applications. This discovery offers a new strategy for hepatocellular carcinoma treatment with the potential to improve patient outcomes.

Immune checkpoint inhibitors (ICIs) are playing a significant role in the treatment of hepatocellular carcinoma (HCC). This study aims to explore the prognostic value of alpha-fetoprotein (AFP) and initial tumor shape irregularity in patients treated with ICIs.

In this retrospective, multi-center study, 296 HCC patients were randomly divided into the training set and the validation set in a 3:2 ratio. The training set was used to evaluate prognostic factors and to develop an easily applicable ATSI (AFP and Tumor Shape Irregularity) score, which was verified in the validation set.

The ATSI score was developed from two independent prognostic risk factors: baseline AFP ≥ 400 ng/ml (HR 1.73, 95% CI 1.01-2.96, P = 0.046) and initial tumor shape irregularity (HR 1.94, 95% CI 1.03-3.65, P = 0.041). The median overall survival (OS) was not reached (95% CI 28.20-NA) in patients who met no criteria (0 points), 25.8 months (95% CI 14.17-NA) in patients who met one criterion (1 point), and 17.03 months (95% CI 11.73-23.83) in patients who met two criteria (2 points) (P = 0.001). The median progression-free survival (PFS) was 10.83 months (95% CI 9.27-14.33) for 0 points, 8.03 months (95% CI 6.77-10.57) for 1 point, and 5.03 months (95% CI 3.83-9.67) for 2 points (P < 0.001). The validation set effectively verified these results (median OS, 37.43/24.27/14.03 months for 0/1/2 points, P = 0.028; median PFS, 13.93/8.30/4.90 months for 0/1/2 points, P < 0.001).

The ATSI score can effectively predict prognosis in HCC patients receiving ICIs.

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.

Hepatocellular carcinoma (HCC) is the most frequent kind of liver cancer with high morbidity and mortality rates worldwide. Altered expression of BUB1 (budding uninhibited by benzimidazole 1) gene leads to chromosome instability and aneuploidy. This study investigated the expression of BUB1 and its prognostic value as well as its correlation with immune cell infiltration and immune checkpoints in HCC.

Using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, we found that BUB1 was up-regulated in HCC, thus prompting us to validate this observation by immunohistochemistry on 57 HCC paraffin embedded tissues from Wuxi No.2 People's Hospital. Kaplan-Meier survival analysis revealed that HCC patients with high BUB1 expression had shorter overall survival (OS) time as well as progression-free interval (PFI), and disease-specific survival (DSS) time compared to the patients with low BUB1 expression. Besides, STRING database showed that the top 10 co-expression genes were mainly involved in the regulation of cell division during the mitosis. Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that BUB1 had a connection to cancer related pathways. Lastly, The Tumor Immune Estimation Resource (TIMER) analysis found that BUB1 was positively related to immune cell infiltration and some immune checkpoint gene in HCC.

Not applicable.

Our present study demonstrated that BUB1 is a potential prognostic biomarker, and BUB1 may play a role in the tumor immune microenvironment in HCC.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death that has limited treatment options for advanced stages. Although PD-1 inhibitors such as nivolumab and pembrolizumab have been approved for advanced HCC treatment, their effectiveness is often hampered by the immunosuppressive tumor microenvironment (TME), which is due to hypoxia-driven CXCL12/CXCR4 axis activation. In this study, we developed 807-NPs, lipid-coated tannic acid (TA) nanoparticles that encapsulate BPRCX807, a potent CXCR4 antagonist to target HCC. 807-NPs enhance the pharmacokinetics and improve the tumor availability of BPRCX807 without causing systemic toxicity. Our findings show that 807-NPs block the CXCR4/CXCL12 pathway, inhibiting Akt and mTOR activation in HCC cells and M2 macrophages and promoting their repolarization toward the antitumor M1 phenotype. In orthotopic murine HCC models, systemic administration of 807-NPs significantly remodeled the immunosuppressive TME by reprogramming tumor-associated macrophages (TAMs) toward an immunostimulatory phenotype and promoting cytotoxic T-cell infiltration into tumors. This led to suppressed primary tumor growth and metastasis, while enhancing the efficacy of cancer immunotherapies, including PD-1 blockade and whole-cancer cell vaccines, by promoting T-cell activation. Our work demonstrates the potential of using nanotechnology to deliver CXCR4 antagonists for cancer immunotherapy.

Fibrosis is a pathological condition characterised by excessive accumulation of extracellular matrix (ECM) components, particularly collagens, leading to tissue scarring and organ dysfunction. In fibrosis, an imbalance between collagen synthesis (fibrogenesis) and degradation (fibrolysis) results in the deposition of fibrillar collagens disrupting the structural integrity of the ECM and, consequently, tissue architecture. Fibrosis is associated with a wide range of chronic diseases, including cirrhosis, kidney fibrosis, pulmonary fibrosis, and autoimmune diseases. Recently, the concept of "hot" and "cold" fibrosis has emerged, referring to the immune status within fibrotic tissues and the nature of fibrogenic signalling. Hot fibrosis is characterised by active immune cell infiltration and inflammation, while cold fibrosis is associated with auto- and paracrine myofibroblast activation, immune cell exclusion and quiescence. In this article, we explore the relationship between hot and cold fibrosis, the role of various types of collagens and their biologically active fragments in modulating the immune system, and how serological ECM biomarkers can help improve our understanding of the disease-relevant interactions between immune and mesenchymal cells in fibrotic tissues. Additionally, we draw lessons from immuno-oncology research in solid tumours to shed light on potential strategies for fibrosis treatment and highlight the advantage of having a "hot fibrotic environment" to treat fibrosis by enhancing collagen degradation through modulation of the immune system.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, largely because of its ability to reshape the tumor microenvironment and evade immune surveillance.

CX3CL1 expression in HCC tumor tissues was assessed via immunohistochemistry, while plasma levels were quantified using enzyme-linked immunosorbent assays (ELISAs). CX3CR1-positive immune cell infiltration was analyzed by immunofluorescence. The associations among CX3CL1 expression, CX3CR1-positive cell infiltration, and patient prognosis were examined. Additionally, cell-based assays were conducted to evaluate the impact of CX3CL1 amplification on the expression of myeloid-derived suppressor cell (MDSC)-recruiting factors.

Elevated CX3CL1 levels were significantly correlated with increased MDSC infiltration in the tumor microenvironment and poorer patient prognosis. CX3CL1 amplification led to the upregulation of MDSC-recruiting factors, suggesting a potential mechanism for immune evasion.

These findings highlight the possible involvement of CX3CL1 in HCC progression via MDSC recruitment, suggesting that it is a promising therapeutic target for promoting antitumor immunity. Further studies are needed to confirm these findings and explore potential therapeutic strategies.

Immunotherapy, exemplified by immune checkpoint blockade (ICB), has been extensively employed in antitumor treatments. Nevertheless, its efficacy in addressing low-immunogenic tumors has not yielded satisfactory results, primarily due to the depletion and inadequate infiltration of effector T cells within the tumor microenvironment (TME). Here, we construct an injectable water-in-oil emulsion hydrogel to load clinically used Celastrol (Gel@Cel), which addresses the limitations of Cel's hydrophobicity. Cel can both inhibit tumor cell proliferation and promote tumor cell apoptosis, while simultaneously inducing immunogenic cell death, through activation of the AKT and MAPK pathways. In a model of clinically refractory hepatocellular carcinoma with malignant ascites, intraperitoneal administration of Gel@Cel significantly inhibits tumor progression and activates antitumor immune effects through lipase-controlled release of Cel, as compared to free Cel. Intriguingly, the Gel@Cel induces the activation of dendritic cells, resulting in the infiltration of cytotoxic T cells in the TME of ascites. Furthermore, the administration of Cel increases the expression of programmed cell death protein ligand-1 (PD-L1) in tumor cells. Moreover, combining the PD-1 antibody (αPD-1) with Gel@Cel further enhances the antitumor effect and amplifies the immune activation. In conclusion, Gel@Cel exhibits promising therapeutic potential in the treatment of low-immunogenic tumors, especially when combined with ICB therapy.

Atezolizumab plus bevacizumab demonstrates a significant improvement in overall survival and progression-free survival compared with sorafenib in patients with unresectable hepatocellular carcinoma (HCC). The combined usage of these two medications could result in substantial consumption of resources, primarily due to their exceptionally high costs. The current study aims to evaluate the cost-effectiveness of atezolizumab plus bevacizumab as a first-line treatment for advanced HCC from the perspective of payers in developed and developing countries.

A partitioned survival model was constructed to evaluate the cost-effectiveness of atezolizumab plus bevacizumab versus sorafenib as a first-line treatment for advanced HCC. The efficacy and safety data incorporated within the model were derived from the IMbrave150 trial. Costs and utilities were extracted from published sources.

Atezolizumab plus bevacizumab versus sorafenib.

Estimates were calculated for costs, life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER) for both treatment strategies. One-way sensitivity, probabilistic sensitivity, expected value of perfect information (EVPI), subgroup and scenario analyses were conducted.

The combination therapy of atezolizumab and bevacizumab results in an additional 0.72 life-years/0.57 QALYs in the USA and 0.64 life-years/0.47 QALYs in China compared with standard sorafenib treatment, although with a significant increase in costs, yielding an average ICER of US$253 247.07/QALY in the USA and US$181 552.71/QALY in China. The probability sensitivity analysis indicated that atezolizumab plus bevacizumab demonstrated a 13.60% likelihood of cost-effectiveness in the USA, whereas this likelihood is negligible (0%) in China. The expected value of uncertainty, as quantified by the EVPI, was estimated at approximately US$3658.41/patient in the USA and US$0/patient in China. The ICER was most sensitive to the cost of subsequent treatment in the USA, and most sensitive to the cost of atezolizumab in China. In scenario analyses, the atezolizumab plus bevacizumab treatment becomes favourable when the cost of atezolizumab decreases to 67.85% and 18.45% of its original price in the USA and China, respectively.

The atezolizumab plus bevacizumab is unlikely to be cost-effective compared with sorafenib for patients with unresectable HCC in the context of the USA and China. The implementation of significant reductions in drug prices may render the treatment economically viable.

Hepatic arterial infusion chemotherapy (HAIC) was an effective treatment for advanced hepatocellular carcinoma (HCC), and its effectiveness in combination with targeted immunotherapy regimens was controversial. This meta-analysis was performed to evaluate the efficacy of adding HAIC to lenvatinib in combination with programmed death-1 (PD-1) inhibitors.

Literature related to the efficacy of HAIC in combination with lenvatinib plus PD-1 inhibitors in the treatment of advanced HCC was searched through PubMed, Cochrane Library, Embase, and Web of Science databases. TSA was used to control for the risk of random error and assess whether the meta-analysis evidence was conclusive.

Eight relevant papers with a total of 1244 patients. Compared with the L-P treatment group, the H-L-P treatment group significantly prolonged OS (hazard ratio [HR] 2.11 [95 % confidence interval (CI) 1.82-2.44]; p < 0.001) and PFS (HR 1.91 [95 % CI 1.67-2.17]; p < 0.001) and improved ORR (risk ratio [RR] 2.20 [95 % CI 1.74-2.78]; p < 0.001) and DCR (RR 1.28 [95 % CI 1.15-1.42]; p < 0.001) in patients with advanced HCC. TSA analysis indicated that further trials were unnecessary, preliminary positive results were promptly obtained. Prognostic factor analysis demonstrated that extrahepatic metastasis were common independent risk factor for OS and PFS. The rate of adverse events (AEs) was higher in the H-L-P treatment group than in the L-P treatment group.

HAIC combined with lenvatinib plus PD-1 inhibitors markedly extended OS and PFS, particularly in patients without extrahepatic metastases. Furthermore, it markedly enhanced ORR and DCR in patients with HCC.

The battle against cancer has evolved over centuries, from the early stages of surgical resection to contemporary treatments including chemotherapy, radiation, targeted therapies, and immunotherapies. Despite significant advances in cancer treatment over recent decades, these therapies remain limited by various challenges. Immune checkpoint inhibitors (ICIs), a cornerstone of tumor immunotherapy, have emerged as one of the most promising advancements in cancer treatment. Although ICIs, such as CTLA-4 and PD-1/PD-L1 inhibitors, have demonstrated clinical efficacy, their therapeutic impact remains suboptimal due to patient-specific variability and tumor immune resistance. Cell death is a fundamental process for maintaining tissue homeostasis and function. Recent research highlights that the combination of induced regulatory cell death (RCD) and ICIs can substantially enhance anti-tumor responses across multiple cancer types. In cells exhibiting high levels of recombinant solute carrier family 7 member 11 (SLC7A11) protein, glucose deprivation triggers a programmed cell death (PCD) pathway characterized by disulfide bond formation and REDOX (reduction-oxidation) reactions, termed "disulfidptosis." Studies suggest that disulfidptosis plays a critical role in the therapeutic efficacy of SLC7A11high cancers. Therefore, to investigate the potential synergy between disulfidptosis and ICIs, this study will explore the mechanisms of both processes in tumor progression, with the goal of enhancing the anti-tumor immune response of ICIs by targeting the intracellular disulfidptosis pathway.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, especially in advanced stages where limited treatment options result in poor prognosis. The immunosuppressive tumor immune microenvironment (TIME), characterized by low immune cell infiltration and exhaustion, limits immunotherapy efficacy. To address this, our study investigates the role of C-C motif chemokine ligand 3 (CCL3) in modulating the HCC TIME.

We analyzed CCL3 expression in human HCC samples from The Cancer Genome Atlas database, focusing on its correlation with inflammatory gene signatures and immune cell infiltration. High-dimensional single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence were used to investigate CCL3's effects on macrophage function and T cell activation. The biological impact of CCL3 on macrophages was assessed using co-culture systems, confocal imaging, metabolite detection, and inhibition assays. Preclinical HCC models and ex vivo tumor fragment assays further explored how CCL3 modulates immune responses and enhances immune checkpoint blockade efficacy.

Our study shows that CCL3 is suppressed in the tumor microenvironment and positively correlates with immune infiltration and inflammatory responses. Targeted liver delivery of rAAV-Ccl3 reprograms the immune microenvironment in HCC, promoting immune cell recruitment and tertiary lymphoid structure formation, thus suppressing tumor growth via immune engagement. Through scRNA-seq, flow cytometry, and multiplex immunofluorescence, we found that CCL3 enhances macrophage antigen uptake and activates cytotoxic T cells. In vivo and in vitro experiments confirmed that CCL3 facilitates T cell infiltration and upregulates MHC II expression on macrophages, enhancing antigen presentation. The CCL3-CCR5 pathway also boosts macrophage metabolism, increasing lysosomal activity and antigen uptake, thereby strengthening adaptive immune responses and increasing sensitivity to immune checkpoint blockade therapies in preclinical models.

This study highlights the pivotal role of CCL3 in reshaping the TIME and enhancing antitumor immunity in HCC. By promoting immune cell recruitment and enhancing antigen presentation, CCL3 demonstrates significant potential to improve the efficacy of immunotherapy, particularly in combination with immune checkpoint inhibitors. Targeting CCL3 may help to overcome the immunosuppressive TIME in HCC and improve patient outcomes.

Liver cancer, particularly hepatocellular carcinoma (HCC), is one of the most common and aggressive malignancies worldwide. Immunotherapy has shown promising results in treating HCC, but its efficacy is often limited by complex mechanisms of immune evasion. Post-translational modifications (PTMs) of proteins play a critical role in regulating the immune responses within the tumor microenvironment (TME). These modifications influence protein function, stability, and interactions, which either promote or inhibit immune cell activity in cancer. In this mini-review, we explore the diverse PTMs that impact immune evasion in liver cancer, including glycosylation, phosphorylation, acetylation, and ubiquitination. We focus on how these PTMs regulate key immune checkpoint molecules such as PD-L1, CTLA-4, and the TCR complex. Furthermore, we discuss the potential of targeting PTMs in combination with existing immunotherapies to enhance the effectiveness of treatment in HCC. Understanding the role of PTMs in immune regulation may lead to the development of novel therapeutic strategies to overcome resistance to immunotherapy in liver cancer.

Previous studies evaluating antiangiogenic agents plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma (HCC) have shown encouraging results. This study was conducted to investigate the efficacy and safety of donafenib combined with sintilimab (Don-Sin) for advanced HCC.

This was a single-center, single-arm phase II trial recruiting patients with BCLC stage C HCC. A safety run-in cohort was planned with the first 6 patients receiving oral donafenib 200 mg twice daily and intravenous sintilimab 200 mg once every 3 weeks. Dose-limiting toxicities (DLTs) were evaluated to determine the recommended dose of donafenib for those enrolled thereafter. The primary endpoint of this study was progression-free survival (PFS) per mRECIST.

30 patients were enrolled. As 3 patients (50.0%) experienced DLTs during safety run-in, the initial dose of donafenib was adjusted to 200 mg once daily for subsequent patients. The primary endpoint was met with a median PFS of 6.2 (95% confidence interval [CI], 4.4-8.0) months per mRECIST (6.3 [95% CI, 5.4-7.2] months per RECIST 1.1). The objective response rate was 23.3% per mRECIST and 16.7% per RECIST 1.1, while the disease control rate reached 76.7% per mRECIST/RECIST 1.1. The median overall survival was 16.0 (95% CI, 13.5-18.5) months. Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%) and grade 3 TRAEs were observed in 9 patients (30.0%).

Don-Sin showed promising antitumor effects with an acceptable safety profile in patients with advanced stage HCC. The preliminary findings need to be further evaluated in phase III randomized controlled trials.

ClinicalTrials.gov (identifier: NCT05162352; date of registration: December 4, 2021).

NUAK1 is associated with metastasis and drug resistance in hepatocellular carcinoma (HCC). However, little is known about the immune functions of NUAK1 in HCC. Therefore, the aim of this study was to elucidate the novel role of NUAK1 in facilitating immune evasion in HCC and to investigate the mechanisms underpinning this process.

The levels of NUAK1 expression and the infiltration of CD8+ T cells were assessed in tumor tissues from HCC patients and mice xenograft model. HCC cell lines were used to validate the role of NUAK1 in regulating the transcription of PD-L1, the diethylnitrosamine-induced HCC model was established and the expression levels of NUAK1 and PD-L1 proteins in the rat livers were detected. Western blotting, immunofluorescence, real time PCR, and immunohistochemical staining were used to investigate the underlying mechanisms by which NUAK1 regulates PD-L1 expression in hepatocellular carcinoma.

NUAK1 expression was negatively correlated with CD8+ T cell infiltration in tumor tissues from HCC patients and mice xenograft model. Both gain and loss of functions have identified NUAK1 promoted PD-L1 expression at transcriptional level in HCC cells. The increased expression of NUAK1 and PD-L1 proteins were observed in the rat livers of diethylnitrosamine-induced HCC model. Moreover, overexpression of NUAK1 promotes GSK3β Ser9 phosphorylation, β-catenin expression and nuclear accumulation in HCC cells. By contrast, knockdown of NUAK1 has opposite effects. Inhibition of GSK3β activity significantly promoted β-catenin expression and PD-L1 expression in HCC cells. IHC analyses of tumor tissues from HCC patients suggested that the levels of p-GSK3β and β-catenin were positively correlated with NUAK1 expression. Knockdown of β-catenin also reversed NUAK1-mediated PD-L1 expression in HCC cells.

This study revealed a novel role for NUAK1, which promotes the transcriptional expression of PD-L1 by activating GSK3β/β-catenin signaling pathway, leading to immune escape of hepatocellular carcinoma. Registry and the registration no. of the study/trial: Not applicable.

The liver is one of the most frequent sites of primary malignancies in humans. Hepatocellular carcinoma (HCC) is one of the most prevalent solid tumors with poor prognosis. Current treatments showed limited efficacy in some patients, and, therefore, alternative strategies, such as immunotherapy, cancer vaccines, adoptive cell therapy (ACT), and recently chimeric antigen receptors (CAR)-T cells, are developed to offer better efficacy and safety profile in patients with HCC. Unlike other ACTs like tumor-infiltrating lymphocytes (TILs), CAR-T cells are equipped with engineered CAR receptors that effectively identify tumor antigens and eliminate cancer cells without major histocompatibility complex (MHC) restriction. This process induces intracellular signaling, leading to T lymphocyte recruitment and subsequent activation of other effector cells in the tumor microenvironment (TME). Until today, novel approaches have been used to develop more potent CAR-T cells with robust persistence, specificity, trafficking, and safety. However, the clinical application of CAR-T cells in solid tumors is still challenging. Therefore, this study aims to review the advancement, prospects, and possible avenues of CAR-T cell application in HCC following an outline of the CAR structure and function.

Liver cancer exhibits diverse molecular characteristics and distinct immune cell infiltration patterns, which significantly influence patient outcomes. In this study, we thoroughly examined the liver cancer tumor environment by analyzing data from 419,866 individual cells across nine datasets involving 99 patients. By categorizing patients into different groups based on their immune cell profiles, including immune deficiency, B cells-enriched, T cells-enriched and macrophages-enriched, we better understood how these cells change in various patient subgroups. Our investigation of liver metastases from intestinal cancer uncovered a group of mast cells that might promote metastasis through pathways like inositol phosphate metabolism. Using genomic and clinical data from The Cancer Genome Atlas, we identified specific cell components linked to tumor characteristics and genetics. Our detailed study of cancer-associated fibroblasts (CAFs) revealed how they adapt and acquire new functions in the tissue environment, highlighting their flexibility. Additionally, we found a significant connection between CAF-related genes and the prognosis of hepatocellular carcinoma patients. This research provides valuable insights into the makeup of the liver cancer tumor environment and its profound impact on patient outcomes, offering fresh perspectives for managing this challenging disease.