Chimeric antigen receptor-natural killer (CAR-NK) therapy represents an emerging new direction in fighting against cancer. In recent years, it has attracted significant attention, largely due to its notable safety advantages over CAR-T cell therapy and its potential for reduced side effects. In this article, we will review the recent preclinical advances and translational challenges in CAR-NK therapy for the treatment of hepatocellular carcinoma (HCC). Several preclinical studies have successfully demonstrated that targeting HCC-associated tumor antigens such as glypican-3 and cluster of differentiation 147 (CD147) could exert a strong anti-tumor efficacy. However, only a few studies have entered the clinical stage, with none having progressed to late-phase trials. The clinical translation of CAR-NK in HCC is mainly hindered by significant challenges, including the immunosuppressive tumor microenvironment, inefficient tumor trafficking, tumor heterogeneity, and poor persistence of infused cells. To overcome these barriers, researchers have been exploring different innovative strategies such as disrupting the transforming growth factor-β signaling, engineering homing chemokine receptors, developing multi-specific CARs, and enhancing persistence with cytokine support (e.g., interleukin-15). Further ongoing research is important to optimize the CAR constructs and identify effective combination approaches to enhance the overall treatment efficacy.

Aim: To identify factors influencing liver-controlled attenuation parameter (CAP, dB/m) and establish its optimal diagnostic thresholds for hepatic steatosis grading in metabolic dysfunction-associated steatotic liver disease (MASLD).

Methods: A total of 758 prospectively enrolled MASLD patients at Zhongshan Hospital, Shanghai, China (September 2022-June 2023) were randomized into a training cohort (n = 619) and a validation cohort (n = 139), stratified by body mass index (BMI: normal-weight < 25 kg/m²; overweight ≥ 25 kg/m²). Demographics, laboratory parameters, CAP, and magnetic resonance imaging (MRI) proton density fat fraction (PDFF) were recorded. Using MRI-derived PDFF (MRI-PDFF) as the reference, receiver operating characteristic (ROC) analysis was performed to establish CAP thresholds for steatosis grades.

Results: In the training cohort, multivariate analysis showed that CAP was correlated with uric acid, glucose, and high-density lipoprotein (HDL) in normal-weight patients, and with alanine aminotransferase (ALT), total cholesterol (TC), and BMI in overweight patients. Overall cohort CAP thresholds were: S1, 283.5 dB/m [area under the curve (AUC) = 0.880]; S2, 311.5 dB/m (AUC = 0.712); S3, 328.5 dB/m (AUC = 0.799). Normal-weight thresholds: S1, 259.5 dB/m (AUC = 0.922); S2-3, 323.5 dB/m (AUC = 0.779). Overweight thresholds: S1, 304.0 dB/m (AUC = 0.829); S2, 311.5 dB/m (AUC = 0.677); S3, 328.5 dB/m (AUC = 0.767). Validation confirmed robust diagnostic performance.

Conclusion: CAP correlates significantly with metabolic factors (glucose, HDL) and shows a trend toward association with uric acid (P = 0.073) in normal-weight MASLD patients, and with liver markers/metabolic factors (BMI, ALT, TC) in overweight patients. CAP demonstrates good diagnostic accuracy for grading the severity of hepatic steatosis in MASLD, particularly for mild to moderate steatosis.

Highlights

1. Study of 758 MASLD patients stratified by BMI to identify factors influencing CAP and its diagnostic value for hepatic steatosis, using MRI-derived PDFF as reference.
2. CAP correlates with glucose, HDL, and uric acid in normal-weight patients, and with ALT, total cholesterol (TC), and BMI in overweight patients.
3. BMI-specific CAP thresholds were established, with the highest diagnostic performance in normal-weight individuals (AUC = 0.922 for S1).
4. Validation confirmed robust diagnostic accuracy (Youden index 0.81-0.83), supporting CAP as a practical non-invasive tool for grading mild-to-moderate steatosis.

The liver is the most common metastatic site of gastric cancer, and liver metastasis is one of the leading causes of death in patients with gastric cancer, characterized by a complex and unique tumor microenvironment (TME). The molecular classification and pathological characteristics of gastric cancer provide a basis for its research and treatment. The dynamic remodeling mechanisms of the TME involve multiple aspects, including stromal cell reprogramming, immune microenvironment characteristics, and regulation of the extracellular matrix and mechanical forces. The clinical challenges of gastric cancer liver metastasis (GC-LM) are severe, and effective intervention strategies need to be proposed, including overcoming physical barriers, precision therapies targeting the microenvironment, and biomarker development. In the future, integrating multi-omics and spatial dynamic analyses and establishing a molecular pathology-clinical translation feedback loop will be essential directions and challenges in this field. This review summarizes the research progress on the TME of GC-LM from clinical molecular pathology to precision medicine, aiming to provide a theoretical basis and new insights for the precision therapy of GC-LM.

Aim: Aberrant metabolism represents a hallmark feature of malignancies, which is crucial for facilitating adenosine triphosphate (ATP) production and biosynthesis of macromolecules that sustain cell proliferation, differentiation, and survival. In the context of tumorigenesis, fatty acids (FAs) have garnered substantial attention due to their dual role as secondary messengers and energy substrates. Notably, the pivotal role of FA metabolism in hepatocellular carcinoma (HCC) progression has been extensively explored. Therefore, this study aims to investigate the contributions of FA metabolism in the immunotherapy of HCC, which remain undefined.

Methods: We analyzed messenger RNA expression and genetic alterations of regulators of FA metabolism from public HCC datasets. Based on their FA metabolism profiles, patients were classified into two distinct molecular subtypes: cluster A and cluster B. Using subtype-derived differentially expressed genes, we established an unsupervised FA_score algorithm. Immune infiltration analysis and prognostic screening of 2,484 immune genes were integrated to develop a risk model, ultimately classifying patients into four integrated subtypes: mixed index (MI)-1 to MI-4.

Result: Cluster B exhibited significantly worse overall survival than cluster A. Higher FA_score correlated with shorter survival and increased infiltration of immunosuppressive cells. The MI-2 subgroup showed abundant CD4+ T cells, myeloid-derived suppressor cells, and regulatory T cells, indicating strong immunosuppression and poor prognosis, suggesting limited benefit from immunotherapy.

Conclusion: We developed a novel classification system integrating FA metabolism and immune features. The MI-2 subtype is characterized by immunosuppression and poor outcomes, highlighting the clinical relevance of FA metabolic patterns in shaping the immune microenvironment and guiding personalized treatment in HCC.

The therapeutic landscape of hepatocellular carcinoma (HCC) is undergoing a substantial transformation driven by advances in systemic therapies and locoregional treatments. High response rates observed with immune checkpoint inhibitors and combination regimens have opened the door to conversion therapy. Initially unresectable or non-curable patients can achieve a tumour downsizing to access potentially curative options such as surgery, ablation, or transplantation. This evolving strategy is framed within the concept of the converse therapeutic hierarchy, which promotes a dynamic, response-guided approach. In this model, every treatment is no longer a terminal option but a potential gateway to curative interventions. This review explores the clinical rationale and current evidence supporting conversion therapy in HCC, detailing systemic regimens, transarterial and percutaneous treatments, and their integration into multimodal strategies. Emphasis is placed on response-guided treatment reassessment, perioperative immunotherapy, and the potential of tailored sequencing to redefine clinical practice in HCC. Barriers such as biological heterogeneity, the lack of predictive biomarkers, and organisational gaps in multidisciplinary coordination remain significant. At the same time, improvements in systemic efficacy, advances in locoregional techniques, and new evidence from real-world data point toward a future in which therapeutic intent is no longer fixed but can evolve according to patient response. Conversion therapy, once aspirational, is becoming a realistic and strategic objective in modern HCC care.

Hepatocellular carcinoma remains a leading cause of cancer-related mortality worldwide. Despite advances in surgical and systemic therapies, recurrence rates remain high, and translational models for therapeutic testing are limited. This review explores the evolving role of ex vivo liver perfusion (EVLP) as a translational platform in hepatoma research, highlighting its applications in tumour modelling, therapeutic testing, and biomarker discovery. A narrative synthesis of recent literature was performed, focusing on EVLP modalities such as normothermic machine perfusion, hypothermic oxygenated perfusion, split-liver perfusion, and segmental perfusion of resected tumour-bearing tissue. EVLP preserves hepatic architecture and metabolic function, enabling real-time study of tumour microenvironments, pharmacological responses, and recurrence mechanisms. Segmental perfusion provides an ethically viable translational model. Overall, EVLP represents a transformative tool in hepatobiliary oncology, bridging the gap between in vitro models and clinical practice, enhancing mechanistic understanding, and accelerating therapeutic innovation.

Hepatocellular carcinoma (HCC) remains a significant global health issue, linked to chronic liver diseases such as viral hepatitis, cirrhosis, and metabolic dysfunction-related steatohepatitis. Early, accurate diagnosis is vital for treatment, but many cases are diagnosed at advanced stage. Contrast-enhanced ultrasound (CEUS) is a valuable, radiation-free tool for real-time liver lesion assessment with high accuracy. This review examines the growing role of ultrasound and CEUS in diagnosing, monitoring, and post-treatment care of HCC. CEUS has sensitivity and specificity similar to computed tomography and magnetic resonance imaging, especially for nodules ≥ 1 cm, and helps clarify uncertain Liver Imaging Reporting and Data System findings. Dynamic CEUS improves diagnosis by allowing microvascular perfusion measurement. Artificial intelligence (AI) and machine learning integration promises automated lesion classification and better consistency. CEUS is especially useful in outpatient and resource-limited settings, enabling quick decision-making and reducing delays. Meta-analyses and studies support CEUS for initial detection and post-treatment follow-up. As advanced ultrasound becomes more accessible, CEUS can be more widely used in hepatology. Future steps include standard protocols, clinician training, and AI integration. Overall, CEUS complements other imaging methods and aids precision medicine in liver cancer management.

Metabolic reprogramming is a fundamental mechanism through which tumor cells reshape their energy metabolism to sustain rapid proliferation. It facilitates malignant growth by reprogramming key pathways, including glycolysis and amino acid metabolism. The tumor microenvironment (TME) is composed of tumor cells, stromal cells, and immune cells. The characteristics of hypoxia, acidity, and nutrient deficiency are mainly driven by the metabolic products and cytokines secreted by tumor cells. This metabolic pressure not only inhibits the functions of immune cells, but also further enhances immune evasion through nutrient competition. Targeting metabolic reprogramming can reverse immunosuppression within the TME and enhance the response to immunotherapy. This article systematically reviews the regulatory mechanisms of metabolic reprogramming in hepatocellular carcinoma and its impact on the TME, while also exploring therapeutic strategies based on metabolic interventions.

The Multiparametric Therapeutic Hierarchy (MTH) has been proposed as an evolution of the Barcelona Clinic Liver Cancer (BCLC) algorithm to better reflect the complexity of real-world hepatocellular carcinoma (HCC) management. While the BCLC often assumes idealised conditions, the MTH explicitly incorporates “treatment unfeasibility” as a variable in clinical decision-making, a concept this review seeks to examine and refine. We propose that unfeasibility should not be limited to absolute contraindications but should be understood as a multidimensional construct comprising four interacting dimensions: (1) Technical Feasibility; (2) Resources; (3) Equity; and (4) Values and Acceptability. This concept of unfeasibility adapts the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence-to-Decision (EtD) framework, originally designed for population-level guideline development, to individual-level clinical reasoning. At the point of care, the five EtD domains (Feasibility, Resources, Acceptability, Equity, and Values and Preferences) converge into a unified assessment of treatment feasibility for the specific patient. A precise mapping between our four dimensions and the original GRADE domains is provided. This approach is complementary to, rather than a departure from, GRADE methodology and is particularly relevant in settings characterised by low or very low certainty of evidence. Our analysis reveals a recurring inverse relationship between therapeutic efficacy and feasibility: the most effective treatments, such as liver transplantation, are often constrained by technical, resource-related, and systemic barriers. This tension results in widespread undertreatment across the HCC population. By defining unfeasibility as a key element of expert reasoning, this framework aims to enhance transparency in how multidisciplinary tumour boards weigh multiple considerations when making individualised treatment decisions under uncertainty, without prescribing decision rules or treatment recommendations.

Liver cancer, particularly hepatocellular carcinoma (HCC), poses a severe global public health threat owing to its high incidence, frequent late-stage diagnosis, and poor 5-year survival rate. Conventional approaches to liver cancer diagnosis and treatment are limited by their reliance on subjective physician experience, uniform and undifferentiated treatment strategies, and imprecise prognostic assessment. This review synthesizes studies published between 2019 and 2025 on the application of multi-modal data in liver cancer care, including computed tomography (CT), magnetic resonance imaging (MRI), pathology, and multi-omics data. We explore the utility of single-modal data analysis including the role of CT or MRI in enhancing diagnostic accuracy and the application of pathological data. Subsequently, the review focuses on multi-modal data fusion strategies, including feature-level, decision-level, and modal-level fusion, which collectively support precision diagnosis, personalized treatment recommendation, and accurate prognosis prediction in clinical practice. Additionally, it addresses critical challenges such as data heterogeneity and low physician acceptance of integrated data-driven tools, while outlining future directions including the development of standardized multi-modal data ecosystems. This review highlights multi-modal data as a core driver of precision liver cancer care, with the objective of accelerating its translation into routine clinical practice.

Kupffer cells, the resident liver macrophages, are characterized by self-renewal capacity and extensive plasticity. Kupffer cells are involved in the regulation of several liver functions such as the maintenance of liver tolerance against antigens arriving at the liver through the portal vein, the autophagy and apoptosis of hepatocytes and other liver sinusoidal cells.and various metabolic functions such as iron homeostasis and lipid metabolism. In acute liver injury, Kupffer cells are involved in both liver damage and resolution. During chronic liver injury, resident and bone marrow-derived macrophages drive either the progression or resolution of fibrosis and cirrhosis. Inevitably, they are implicated in the initiation, progression or defense against hepatocellular carcinoma (HCC) as members of the tumor microenvironment together with bone marrow-derived macrophages. The present review describes the heterogeneity of Kupffer cells and liver-infiltrating macrophages, their functions and their participation in liver cancer with particular emphasis on factors modulating their pro-tumoral and anti-tumoral differentiation. The review is further focused on their involvement in HCC as they participate in the population of tumor-associated macrophages. Finally, the potential use of Kupffer cells and macrophages for the treatment of HCC, including the potentiation of immune checkpoint inhibitors, is presented.

Aim: Oxaliplatin (OXA), a cornerstone chemotherapeutic agent for malignant tumors, can induce hepatic steatosis, inflammation, and fibrosis, meeting the criteria for drug-induced fatty liver disease (DIFLD). However, OXA-induced DIFLD lacks a clear definition and effective interventions. Therefore, our study aimed to verify the OXA-DIFLD link and explore cordycepin’s protective role in DIFLD.

Methods: (1) A retrospective analysis was conducted to compare the degrees of hepatic inflammation, fibrosis, and steatosis among 161 patients with colorectal cancer liver metastasis in the OXA chemotherapy (OCG) and non-chemotherapy (NCG) groups; (2) Fifteen mice were randomly allocated into Control, OXA, and OCordy (OXA + cordycepin) groups. The OXA and OCordy groups received OXA (8 mg/kg, 3 days) injections to induce acute DIFLD; the OCordy group additionally received oral cordycepin (100 mg/kg, 6 days). Liver injury across the three groups was assessed via hepatic pathology, serum biochemical indicators, and oxidative stress markers; (3) Untargeted metabolomics and Data-Independent Acquisition (DIA) proteomics were conducted across the three groups to clarify OXA-induced liver injury mechanisms and pinpoint targets for cordycepin intervention.

Results: (1) Clinical investigations demonstrated markedly elevated hepatic inflammation, fibrosis, and steatosis in the OCG group compared with the NCG group; (2) Animal experiments showed that OXA induced hepatic dysfunction, lipid accumulation, and oxidative stress, which were mitigated by cordycepin; (3) Multi-omics analyses revealed that OXA disrupted lipid metabolism and oxidative stress pathways, whereas cordycepin restored homeostasis by modulating arginine biosynthesis and bile secretion and suppressing α-ketoglutarate levels.

Conclusion: This study characterized OXA-induced DIFLD and validated cordycepin’s protective effects via the α-ketoglutarate-arginine/bile acid axis, offering a foundation for treating OXA-induced liver injury.

FOLFOX (oxaliplatin, leucovorin, 5-fluorouracil)-based hepatic arterial infusion chemotherapy (FOLFOX-HAIC) has emerged as a promising locoregional strategy in the multimodal management of hepatocellular carcinoma (HCC), particularly for patients with intermediate or advanced-stage disease. This narrative review summarizes recent clinical evidence on the application of FOLFOX-HAIC across the therapeutic continuum: in conversion, neoadjuvant, and adjuvant settings. We conducted an analysis based on a search of PubMed, Embase, China National Knowledge Infrastructure (CNKI) and conference abstracts, which incorporated phase II/III trials, retrospective cohort studies, multicenter real-world studies, and meta-analyses. Evidence indicates that FOLFOX-HAIC, especially when combined with targeted therapy and immunotherapy, yields superior objective response rates and higher rates of conversion to curative resection compared to conventional transarterial chemoembolization (TACE). Furthermore, as postoperative adjuvant therapy, it significantly reduces recurrence risk and prolongs survival in high-risk patients, such as those with microvascular invasion. In the neoadjuvant setting, these combinations can induce profound pathological responses, potentially improving outcomes for resectable patients at high risk of recurrence. Consequently, FOLFOX-HAIC represents an evolving cornerstone of HCC therapy. However, current evidence is largely derived from retrospective and small prospective studies, underscoring the urgent need for large-scale phase III randomized controlled trials to standardize regimens, optimize patient selection, and confirm long-term survival benefits.

Hepatocellular carcinoma (HCC) is a malignant tumor with extremely high global morbidity and mortality. Its initiation and progression are tightly associated with the complex tumor microenvironment (TME), which drives immune escape and treatment resistance in liver cancer. In recent years, epigenetic regulation, particularly histone modification mediated by cellular metabolism, has emerged as a critical advance in deciphering tumor malignant behavior and its interaction with the microenvironment. Histone lactylation, a newly identified post-translational modification directly mediated by lactate, offers a novel perspective for understanding how abnormal tumor metabolism (especially the Warburg effect) shapes the immune microenvironment via epigenetic reprogramming. This review elaborates on the role of histone lactylation in HCC progression, focusing on its mechanisms in regulating oncogenic signaling pathways, metabolic reprogramming and reshaping the HCC TME, thereby serving as a core node in metabolic-epigenetic-immune crosstalk. In addition, we summarize the intervention strategies and drug development targeting this modification, and discuss future directions, aiming to provide a basis for the development of novel HCC therapeutic strategies based on metabolic-epigenetic regulation.

Aim: Microvascular invasion (MVI) and recurrence significantly impact hepatocellular carcinoma (HCC) prognosis. This study aims to develop a multi-task deep learning (DL) model using contrast-enhanced computed tomography (CT) to predict preoperative MVI, recurrence-free survival (RFS), and overall survival (OS).

Methods: Preoperative CT scans from 308 patients across five institutions were collected for training and internal validation. A multi-task 3D neural network was trained using a novel augmentation strategy. An independent external cohort (n = 80) from Institution VI was used to rigorously assess generalizability. Model performance was assessed using the concordance index (C-index) for RFS/OS and the F1-score for MVI.

Results: In the training cohort (n = 192), the model achieved an MVI F1 score of 0.739, and C-indices of 0.965 (OS) and 0.869 (RFS). In the internal validation cohort (n = 116), the corresponding values were 0.716, 0.831, and 0.741, respectively. Notably, in the independent external cohort, the model maintained robust performance, with an OS C-index of 0.767, RFS C-index of 0.733, and MVI F1 score of 0.708. Class activation maps confirmed that the model focused on clinically relevant liver regions.

Conclusion: Our interpretable multi-task DL model demonstrates robust predictive capabilities for RFS, OS, and MVI in HCC patients across multiple centers, offering a non-invasive tool to enhance clinical decision-making.

Hepatocellular carcinoma (HCC) is characterized by marked intertumoral and intratumoral heterogeneity, which contributes to highly variable responses to systemic therapy and limits the clinical utility of current biomarker-driven precision strategies. Growing evidence suggests that static molecular profiling alone cannot fully capture the functional determinants of therapeutic response, particularly for immune checkpoint-based treatment. In this review, we discuss the concept of functional precision oncology in HCC and provide a structured framework for positioning patient-derived tumor models across the translational spectrum. We compare long-term expandable patient-derived organoids (PDOs), short-term patient-derived organotypic tumor spheroids (PDOTS), and patient-derived tumor fragments (PDTFs), emphasizing their distinct biological scopes and translational roles. Whereas conventional PDOs support scalable assessment of tumor cell-intrinsic drug sensitivity, organotypic platforms preserve endogenous immune and stromal components and therefore permit direct ex vivo interrogation of immunotherapy responses. We further discuss how functional drug-response data generated from these models can serve as phenotypic ground truth for interpreting multi-omics data and informing computational and AI-assisted predictive frameworks. Finally, we outline key challenges related to standardization, scalability, and clinical integration, and propose a roadmap for incorporating patient-derived functional tumor models into precision therapy development for HCC.

Yttrium-90 (Y-90) radioembolization, via endovascular delivery of high-dose beta radiation microspheres to tumors, is an invaluable locoregional therapy for hepatocellular carcinoma (HCC). Y-90’s limited off-target radiation exposure enables excellent tumor control with a favorable safety profile. Recent developments suggest that combining targeted radioembolization with systemic treatments, such as molecularly targeted therapies and immune checkpoint inhibitors (ICIs), may offer additive or even synergistic benefits, thereby enhancing both local tumor response and immune activation. This review explores the mechanistic rationale, clinical evidence, and therapeutic strategies involving Y-90 combination therapies in HCC. Data from phase I, II, and III trials suggest improved outcomes with Y-90 plus ICI combination therapy compared with monotherapy. By contrast, trials comparing Y-90 and multi-kinase combination inhibitors with monotherapy have yielded mixed results, highlighting the importance of continued research. Challenges remain in patient selection, optimal sequencing, and toxicity management. To date, no randomized clinical trials have directly compared Y-90 alone with Y-90-based combination therapy, but ongoing trials aim to clarify the role of Y-90 in the evolving systemic treatment landscape. This review highlights the potential of Y-90 combination therapies to enhance the multidisciplinary management of HCC and underscores future research priorities to optimize outcomes.

Hepatocellular carcinoma (HCC) is a highly lethal malignancy worldwide and is characterized by a low rate of early detection. In recent years, immune checkpoint inhibitors (ICIs) have been increasingly incorporated into the management of advanced HCC. However, overall response rates remain modest, indicating that immune checkpoint blockade alone is insufficient to overcome the intrinsic immunosuppressive state of HCC. Advances in metabolomics have provided new insights into early detection and therapeutic response evaluation in HCC and have underscored the functional significance of tumor metabolism in disease progression. The metabolic landscape of the HCC tumor microenvironment is predominantly shaped by alterations in glucose, lipid, and amino acid metabolism. These pathways not only support tumor cell energy production and biosynthetic demands but also reprogram local nutrient availability and metabolite composition, thereby continuously reshaping the immune milieu. This metabolic remodeling impairs effector immune cell function and facilitates the establishment and maintenance of immunosuppressive cell populations. Accordingly, this review summarizes the role of metabolic reprogramming in tumor immune regulation during HCC development, with a focus on the heterogeneity of metabolic reprogramming and immune regulation across distinct etiological backgrounds. Systematic elucidation of immunometabolic crosstalk may enhance the precision and translational potential of combination therapeutic strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis and strongly associated with cardiometabolic risk factors, including obesity, type 2 diabetes (T2D), and hypertension. Its global prevalence continues to rise, and pharmacologic interventions are gaining attention, particularly the incretin-based agents, which offer benefits beyond weight loss and glycemic control, such as potential improvements in hepatic inflammation and fibrosis. This review collates current evidence on incretin-based therapies for MASLD and metabolic dysfunction-associated steatohepatitis (MASH), emphasizing their therapeutic potential and the need for robust data on long-term hepatic outcomes. A comprehensive literature search across multiple databases was conducted to evaluate the role of incretin-based agents in MASLD/MASH management. Incretin mimetics demonstrate broad metabolic benefits, with growing evidence supporting their ability to resolve steatohepatitis and mitigate liver fibrosis. While weight reduction and improved insulin sensitivity are primary mechanisms, additional pathways may contribute. Gastrointestinal adverse effects are common but generally manageable, allowing preservation of hepatic and cardiometabolic benefits. Early-phase trials reporting reductions in hepatic fat and favorable histologic changes show promising efficacy, however, most data are limited to small phase 2 studies. Large-scale phase 3 trials are essential to confirm effectiveness, establish long-term safety, and guide clinical integration.

Aim: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with heterogeneous responses to immune checkpoint inhibitors (ICIs). Activated CD8⁺ T cell plays pivotal role in antitumor immunity, yet their systematic integration into a prognostic and predictive molecular framework is lacking.

Methods: RNA-seq data from 363 HCC patients in The Cancer Genome Atlas (TCGA) and validation cohorts (GSE76427, GSE14520) were analyzed by single-sample gene set enrichment analysis (ssGSEA). We quantified 28 tumor-infiltrating immune cell subsets and performed consensus clustering based on activated CD8⁺ T cell infiltration. Weighted gene co-expression network analysis (WGCNA) identified a CD8⁺ T cell associated gene module. Cox regression analysis selected 17 hub genes, from which an immune infiltration-based prognostic model was constructed and externally validated. The two risk groups were compared for prognosis, molecular features, and immunotherapy sensitivity using immune, stromal, stemness, and tumor immune dysfunction and exclusion (TIDE) scores.

Results: We determined the proportion of activated CD8⁺ T lymphocytes associated with the coexpression network. Cluster 1 and low-risk groups exhibited higher immune infiltration and better prognosis (P < 0.05) than Cluster 2 and high-risk groups. Indicators of immunotherapy response - including lower mutation frequency, copy-number variations (CNVs), and stemness score, along with higher immune, stromal, and TIDE scores - suggested reduced ICI therapy efficacy in Cluster 1/low-risk groups, whereas the opposite pattern was observed in Cluster 2/high-risk groups.

Conclusion: We established a robust prognostic classifier based on activated CD8⁺ T cell-related genes. This model may aid in identifying HCC patients with poor prognosis who are likely to benefit from immune checkpoint inhibitor therapy.

Aim: This study examined the relationship between Helicobacter pylori (H. pylori) and metabolic dysfunction-associated fatty liver disease (MAFLD) and concurrently evaluated their association with all-cause mortality risk.

Methods: Data were extracted from the Third National Health and Nutrition Examination Survey, which included 5,073 participants with available H. pylori IgG serology [enzyme-linked immunosorbent assay (ELISA)] results and mortality data. Logistic regression was used to assess the relationship between H. pylori seropositivity and MAFLD risk, while Cox proportional hazards regression was used to evaluate all-cause mortality risk, with adjustment for confounders.

Results: Among 5,073 participants, 2,394 (47.2%) tested positive for H. pylori and 1,610 (31.7%) had MAFLD; during a median follow-up of 28.8 years, 1,891 deaths occurred (overall mortality rate 37.3%). H. pylori-seropositive individuals exhibited significantly higher mortality rates than seronegative individuals (43.5% vs. 31.7%, P < 0.001). Multivariate logistic regression confirmed H. pylori seropositivity as an independent risk factor for MAFLD [adjusted odds ratio (OR) = 1.282, 95% confidence interval (CI): 1.126-1.459, P < 0.001]. Multivariate Cox regression revealed that H. pylori seropositivity independently increased mortality risk (adjusted HR = 1.253, 95%CI: 1.139-1.379, P < 0.001), which was consistent across the MAFLD and non-MAFLD subgroups. Kaplan-Meier analysis corroborated significant survival divergence (log-rank, P < 0.001).

Conclusion: This study indicates that H. pylori seropositivity is independently associated with a higher prevalence of MAFLD and greater mortality risk in community-dwelling individuals.

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide. Despite significant improvements in the treatment landscape for advanced HCC in recent years through combination therapies centered on immune checkpoint inhibitors (ICIs), only approximately 20%-30% of patients achieve durable clinical responses. Primary and acquired resistance remain critical bottlenecks limiting broader efficacy. Traditionally, investigations into resistance mechanisms have predominantly focused on the tumor microenvironment (TME), emphasizing the formation of an immune-“cold” niche, the compensatory upregulation of alternative immune checkpoints [e.g., lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT)], and dynamic metabolic reprogramming. However, this tumor-centric perspective fails to fully account for the observed inter-patient heterogeneity in treatment efficacy, suggesting the critical involvement of systemic regulatory factors. Grounded in the unique anatomical and physiological connectivity of the “gut-microbiota-liver axis”, the gut microbiota, as a critical extrahepatic regulatory system, is increasingly recognized for its role in influencing hepatic immune homeostasis and anti-tumor responses. This provides a novel breakthrough for systemically understanding and overcoming immunotherapy resistance in HCC. The gut microbiota systemically regulates immune surveillance in the liver and the immune status of the tumor microenvironment through various mechanisms, including metabolites (such as short-chain fatty acids, secondary bile acids, and tryptophan metabolites), the activation of pattern recognition receptors, and antigen cross-reactivity. Clinical evidence indicates significant differences in gut microbial community structure between responders and non-responders, while antibiotic use may impair the efficacy of ICIs by disrupting microbial homeostasis. Consequently, microbiota-targeted interventions have emerged as promising strategies to reverse immunosuppression and re-sensitize tumors to immunotherapy. Modalities such as fecal microbiota transplantation (FMT), next-generation probiotics/synbiotics, metabolite-based therapies, and engineered bacteria have progressed from concept to early-stage clinical practice, demonstrating initial safety and feasibility. This article systematically reviews the mechanisms and clinical evidence regarding the role of the gut microbiota in immunotherapy resistance for HCC, and discusses its translational prospects as a personalized combination therapeutic strategy, aiming to provide new insights for overcoming bottlenecks in HCC immunotherapy.

Aim: Primary liver cancer (PLC) remains an important public health concern in Anhui Province, China. Whether dietary habits distinctive to this region are associated with the risk of PLC remains to be investigated. This study aimed to identify characteristic dietary patterns among the adult population in Anhui and examine their associations with PLC risk.

Methods: Using data from a geographically representative community sample (n = 2,548), dietary patterns were derived using hierarchical clustering and principal component analysis based on food frequency questionnaires and were structurally validated. A 1:2 matched case-control study (277 PLC cases, 554 controls) was used to assess the associations between these patterns and PLC risk.

Results: Four dietary patterns were identified. The high refined grain-low whole grain pattern [odds ratio (OR) = 4.60; 95% confidence interval (CI): 2.27, 9.33], the alcohol and preserved food co-consumption pattern (OR = 2.41; 95%CI: 1.27, 4.54), and the red meat-poultry-aquatic product pattern (OR = 2.18; 95%CI: 1.22, 3.90) were associated with increased PLC risk. In sensitivity analyses, red meat and Chinese liquor appeared to be primary risk contributors within their respective patterns, whereas whole grains, fruits, vegetable oils, and tea appeared to have protective associations. The diverse plant-based pattern was not significantly associated with PLC risk.

Conclusion: Several dietary patterns reflecting local consumption habits in Anhui were associated with PLC risk. These findings suggest the value of region-specific dietary assessment in elucidating lifestyle contributors to PLC.

Aim: We conducted a systematic synthesis of comparative economic evaluations assessing systemic therapies for hepatocellular carcinoma (HCC) to establish their cost-effectiveness.

Methods: We searched six bibliographic databases for English-language studies published from 2015 through June 2025. Extracted endpoints included counts and types of regimens deemed cost-effective, quality-adjusted life years (QALYs), incremental cost-effectiveness ratios (ICERs), and ICER relative to national willingness-to-pay (WTP) thresholds.

Results: Fifty-four studies met the inclusion criteria, producing four treatment subgroupings and 35 distinct treatment comparisons. QALYs were reported in 96.3% of articles, ICERs in 90.7%, and WTP thresholds in 92.6%. Fourteen regimens (40.0% of comparisons) were judged cost-effective. Regimens that included immunotherapy were more often cost-effective, while lenvatinib outperformed sorafenib in most analyses. Nearly all studies (94.4%) relied, to varying degrees, on data from 14 randomized controlled trials; 48.1% focused on the Chinese healthcare environment; 27.8% used a lifetime horizon; and 38.9% reported a median [interquartile range (IQR)] horizon of 10 (9) years. Only 5.5% adopted a societal perspective.

Conclusion: Less than half of the evaluated systemic therapies were cost-effective, focusing mainly on immunotherapy-based regimens. Harmonized methodological standards are needed to ensure that economic evaluations keep pace with real-world practice as systemic treatments become more widely adopted. [International Platform of Systematic Review and Meta-Analysis Protocols (INPLASY) registration number: 2025100049].

Chronic liver disease constitutes a major global health burden, driven largely by complications of cirrhosis, viral hepatitis and hepatocellular carcinoma. While liver transplantation remains the current definitive treatment, its impact is constrained by organ scarcity, strict eligibility criteria, and lifelong immune-related complications. Through comparison of transplant strategies and decellularization-recellularization protocols, this review evaluates the translational potential of decellularized liver scaffolds, with particular emphasis on their feasibility and reported outcomes in surgical transplantation. Decellularization approaches varied across studies, with differences in preferred cell sources and recellularization outcomes. Thrombogenicity and biliary system reconstruction remain key challenges requiring further investigation. Perfusion-based recellularization in bioreactor systems, provides controlled cell seeding and dynamic culture conditions. In this context, segmental or split liver scaffolds may serve as a viable model for future translational studies. Overall, decellularized liver scaffolds represent a promising bridging strategy to address the current limitations. However, there is heterogeneity between protocols and important translational barriers remain. Further research is required to define the optimal methods through validation in large-animal transplantation studies.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with immunotherapy emerging as a pivotal strategy for advanced disease. However, treatment responses remain highly variable, largely due to the complex and dynamic tumor immune microenvironment (TIME). This review systematically examines the composition, heterogeneity, and function of the TIME of HCC, focusing on the interplay between immunosuppressive cells - such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) - and functional immune cells, including CTLs, NK cells, and DCs. We highlight the spatial and temporal heterogeneity of the TIME, shaped by underlying HCC etiologies, which critically influences immune evasion and therapeutic outcomes. We also evaluate current immunotherapeutic approaches, particularly immune checkpoint inhibitors (ICIs), adoptive cell therapies, and strategies targeting metabolic and microbial remodeling of the TIME. Finally, we discuss emerging combination therapies and future directions aimed at overcoming immunosuppressive barriers to enhance personalized treatment and improve clinical outcomes in HCC. A deeper understanding of TIME biology is essential for developing more effective immunotherapeutic strategies.

Hepatocellular carcinoma (HCC) remains a major cause of global cancer-related mortality, with limited therapeutic options for advanced disease. The advent of immune checkpoint inhibitors (ICIs) has revolutionized HCC treatment; however, only a subset of patients achieve durable responses, underscoring the urgent need for reliable biomarkers to guide precision immunotherapy. Emerging evidence highlights the gut microbiota as a determinant of immunotherapy efficacy through the gut-liver axis. Community diversity, specific microbial taxa, and functional metabolites have been associated with responses to ICIs. Mechanistically, gut microbes influence antigen presentation, T cell activation, and immune tolerance within the hepatic microenvironment. Moreover, microbiota-targeted interventions hold promise for restoring responsiveness in non-responders. This review summarizes the regulatory roles of the gut microbiota in HCC immunotherapy and discusses the potential of microbiota-based strategies as predictive and therapeutic tools. Integrating multi-omics, strain-level analysis, and high-resolution microbial profiling is crucial for realizing microbiota-informed precision immunotherapy in HCC.

Aim: This study aimed to explore the long-term mortality trends in the mortality burden of liver cancer due to alcohol use (LCA) from 1990 to 2021 and assess health inequalities stratified by sex and location, with projections to 2050. The contribution of population growth, age structure and epidemiologic changes to the increase in deaths will also be assessed.

Methods: Bayesian age-period-cohort model was applied to predict age-standardized mortality rate (ASMR). Bayesian spatiotemporal model was utilized to characterize the spatiotemporal distribution of ASMR. Frontier analysis assessed national prevention and control capacity. Decomposition analysis was performed to clarify driving factors of mortality growth.

Results: Global LCA ASMR presented an upward trend during 1990-2021 (AAPC = 0.35). Europe yielded the highest ASMR at 1.34, followed by Africa, while the Americas witnessed the fastest growth. National-level ASMR displayed obvious spatial clustering, with hotspots concentrated in West Africa, Southern Africa and partial Southeast Asian territories. Global LCA ASMR is projected to decline after 2022 and reach 0.93 by 2050. The Americas will undergo an initial rise followed by a subsequent drop in ASMR. Population aging will serve as the predominant driver of growing LCA mortality worldwide. Several nations including Brazil and Somalia are expected to attain relatively low ASMR by 2050.

Conclusion: LCA-related ASMR and health inequalities have aggravated across regions and countries. Targeted regional public health interventions are urgently required, particularly in the Americas and Africa.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), constitute an escalating worldwide health challenge, with prevalence estimates reaching one-quarter of adults globally. The pathophysiology of MASLD/MASH encompasses complex interactions among genetic background, impaired insulin signaling, hepatic lipid accumulation, inflammatory cascades, and progressive fibrosis. Until recently, therapeutic strategies remained limited to lifestyle interventions, with few pharmacological options demonstrating meaningful clinical benefit. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have garnered recognition as potentially revolutionary therapeutic modalities for MASLD/MASH management, offering multifaceted benefits extending beyond glycemic regulation. These medications exert (in)direct hepatic actions by reducing steatosis, attenuating inflammation, and potentially reversing fibrosis, while simultaneously addressing systemic metabolic abnormalities including excessive obesity, insulin resistance, and cardiovascular risk. Recent phase 2 and phase 3 clinical trials have established the therapeutic value of various GLP-1 RAs in improving liver histology and metabolic parameters in patients with MASH. Furthermore, dual-action compounds engaging GLP-1 combined with glucose-dependent insulinotropic polypeptide (GIP) or glucagon pathways, alongside triple agonists incorporating all three receptors activation, have exhibited enhanced therapeutic potential. This review examines the biological mechanisms underlying GLP-1 RA therapy in MASLD/MASH, analyzes the mechanistic distinctions between mono-, dual-, and triple agonists, and synthesizes current clinical evidence supporting their utilization in individuals with this condition.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major driver of chronic liver disease and an increasingly important etiology for hepatocellular carcinoma (HCC). Despite shared metabolic risk factors, MASLD shows marked inter-individual heterogeneity in fibrosis progression, treatment response, and HCC risk, indicating that one-size-fits-all management is insufficient. This narrative review synthesizes advances in precision medicine for MASLD with emphasis on (i) genetic risk stratification (major variants such as PNPLA3 and TM6SF2, protective alleles such as HSD17B13/MARC1, polygenic risk scores (PRS), and ancestry-specific effects); (ii) functional genomics and cell biology [bulk and single-cell expression quantitative trait locus (eQTL) mapping, spatial multi-omics, and cell-state/zonation biology]; and (iii) epigenetic regulation (DNA methylation, histone modifications, and microRNA networks) linking environment to phenotype. We discuss translational implications including biomarker-enabled trial enrichment, risk-based surveillance for advanced fibrosis and HCC, and emerging therapeutics ranging from liver-directed small interfering RNA/antisense oligonucleotides to epigenetic modulators. Finally, we outline how multimodal data integration and artificial intelligence may support clinically deployable risk models and treatment selection. Collectively, the field is moving from population-based management toward individualized prevention and therapy for MASLD and its complications.

The treatment paradigm for hepatocellular carcinoma (HCC) is evolving from traditional stage-based monotherapy toward a synergistic era characterized by the proactive integration of locoregional and systemic therapies. Transarterial chemoembolization (TACE) plus systemic therapy has shown notable synergistic potential, but it also complicates clinical decision-making and trial interpretation. This review briefly outlines advances in TACE and systemic therapy, summarizes key randomized controlled trials of combination therapy, and analyzes core challenges in treatment timing, TACE implementation, endpoint design, and patient selection. Although combination regimens have not consistently demonstrated significant overall survival (OS) benefits in intermediate-to-advanced HCC, improvements in progression-free survival, objective response rate, and other disease-control endpoints have been increasingly reported. Future prospective trials should look beyond drug selection alone and refine combination timing, clinically meaningful endpoints, TACE standardization, and subgroup selection. These refinements may help determine how early disease-control gains can be translated more consistently into durable OS benefit, particularly for patients with intermediate-stage HCC.

With the rapid rise in hepatocellular carcinoma (HCC) incidence associated with metabolic dysfunction-associated steatotic liver disease (MASLD), malnutrition has emerged as a critical comorbidity that affects treatment tolerance and survival outcomes. This review systematically examines the challenges of assessing malnutrition in metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma (MASLD-HCC), its multidimensional pathological mechanisms, and emerging intervention strategies. In current clinical practice, the absence of specialized assessment tools limits the effectiveness of existing evaluation systems in addressing distinct phenotypes, such as obesity and ascites. The underlying mechanisms are complex; disruptions of the “gut-liver-muscle axis”, centered on intestinal dysbiosis, form a key network driving metabolic reprogramming, chronic inflammation, and muscle wasting. Regarding interventions, microbiome-targeted therapies - including fecal microbiota transplantation and probiotics/synbiotics - have shown promise in preclinical studies for modulating immunometabolism and improving nutritional status. However, their translation into routine clinical practice remains constrained by major bottlenecks, including insufficient large-scale randomized controlled trial evidence, uncertainty regarding long-term safety, and inadequate standardization. Future efforts should urgently focus on establishing precise assessment systems and conducting high-quality clinical validation.

Imaging is central to nearly every stage of hepatocellular carcinoma (HCC) management, from surveillance and noninvasive diagnosis to staging, locoregional therapy planning, treatment response assessment, and recurrence monitoring. Recent progress begins with imaging hardware but depends just as much on acquisition design, reconstruction, quantification, harmonization, and workflow integration. This narrative review examines how ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear or hybrid imaging have changed HCC care, while separating clinically established tools from technologies that remain largely translational. Ultrasound has advanced beyond screening through contrast-enhanced ultrasound (CEUS), Kupffer-phase agents, elastography, and fusion navigation. CT has progressed through spectral imaging, deep learning reconstruction, and cone-beam guidance, whereas photon-counting CT remains promising but early. MRI has consolidated its role through 3T platforms, multichannel coils, accelerated acquisitions, hepatobiliary contrast agents, diffusion-based imaging, magnetic resonance elastography (MRE), and abbreviated protocols. Positron emission tomography remains constrained by tracer biology in early HCC, although novel tracers and positron emission tomography (PET)/MRI broaden selected applications. Across modalities, imaging advances are most useful when acquisition and biomarker extraction are reproducible enough to support the Liver Imaging Reporting and Data System (LI-RADS), treatment response assessment, and downstream clinical decisions. Evidence is strongest for CEUS, gadoxetic acid-enhanced MRI, MRE for selected risk questions, and image-guided interventional platforms, whereas spectral CT has growing selected-use evidence but still requires broader standardization of quantitative thresholds. By contrast, radiomics, deep learning, advanced diffusion models, photon-counting CT, and theranostic-oriented molecular imaging still face important barriers related to external validity, harmonization, and clinical qualification.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a growing global health burden, with prognosis determined by dual adverse outcomes: hepatic progression to liver-related events (LREs) and extrahepatic complications, particularly cardiovascular disease (CVD), chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and extrahepatic malignancies. Accurate noninvasive prognostic assessment is therefore essential for risk stratification and individualized management. This review summarizes recent advances in noninvasive tools for predicting outcomes in MASLD. Serum-based models, spanning from established indices to emerging multi-omics and genetic markers, show robust performance for risk stratification. Imaging techniques, notably vibration-controlled transient elastography (VCTE) and magnetic resonance elastography (MRE), along with their derivative models, provide quantitative liver stiffness measurements with established prognostic value. The two-step sequential approach has been validated for integrated risk assessment. Importantly, the utility of these tools extends beyond hepatic risk stratification to the evaluation of extrahepatic complications. Despite this progress, key challenges remain: population-related heterogeneity in model performance, limited clinical applicability of complex models, and a lack of dynamic monitoring strategies. Future research should focus on multi-ethnic validation, the development of dynamic prediction models incorporating longitudinal data, and the integration of artificial intelligence (AI) to enable precision management across the full disease course.

Transarterial chemoembolization (TACE) is an important treatment for intermediate-stage hepatocellular carcinoma (HCC) that often needs to be repeated. However, the optimal number of treatments remains unclear, and the relationship between repeated TACE and patient prognosis is complex and needs to be systematically investigated. Evidence shows that the initial efficacy of TACE is significant; however, with an increase in the number of treatments, the objective response rate of the tumor decreases, and TACE-related liver injury accumulates, which becomes a key factor restricting the long-term survival of patients with HCC. In recent years, the new paradigm of TACE combined with targeted therapy plus immunotherapy has shown significant advantages, improving the tumor remission rate, reducing the number of TACE required, and protecting liver function. In terms of prognosis prediction, the model is evolving from a static model based on baseline characteristics to a dynamic model that integrates treatment response. Frontier research has further explored prognostic prediction models based on genomics, radiomics, and machine learning, providing a direction for achieving higher accuracy of individualized prognostic prediction. This narrative review aims to synthesize the current evidence, explore the relationship between the number of TACE treatments and the prognosis of HCC patients, compare TACE alone versus TACE combined with systemic therapy, and review the methodological progress of prognosis-prediction models.

Against the background of the growing global burden of obesity and metabolic disease, metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a leading cause of chronic liver disease worldwide. Simultaneously, many patients remain affected by chronic hepatitis C virus (HCV) infection or its long-term sequelae, reshaping the spectrum of liver disease in the direct-acting antiviral era. HCV may directly induce hepatic steatosis through genotype-specific mechanisms, whereas MASLD promotes steatosis through systemic metabolic dysregulation. Both pathways can independently cause liver injury, and their coexistence may accelerate fibrosis progression and increase the risk of hepatocellular carcinoma (HCC). Emerging evidence indicates that hepatic steatosis before and after sustained virologic response (SVR) is associated with suboptimal fibrosis regression and persistent HCC risk. These findings highlight the need for integrated clinical management incorporating metabolic optimisation and individualised surveillance. Patients with advanced fibrosis, persistent metabolic dysfunction, or residual steatosis remain at increased risk of HCC despite viral eradication and should not be uniformly classified as low risk. This review examines the biological and clinical intersections between chronic HCV infection and MASLD, focusing on fibrosis progression, hepatocarcinogenesis, and residual HCC risk after SVR. It also emphasises the importance of identifying and managing MASLD in patients with current or previous HCV infection to reduce long-term complications and improve clinical outcomes.