Cancers doi: 10.20517/2394-5079.2025.85

Authors: Luca Risi,Marco Cantamessa,Lorenzo Pavia,Luca Viganò

Aim: Intrahepatic cholangiocarcinoma (iCCA) is a rare liver malignancy with poor prognosis. Surgery remains the cornerstone of treatment; however, systemic therapy may enable tumor downsizing for secondary resectability in initially unresectable patients or serve as neoadjuvant treatment in high-risk resectable cases. This study aimed to systematically summarize the literature to clarify the outcomes of conversion and neoadjuvant systemic therapy in iCCA.

Methods: We conducted a systematic review of English-language studies published before August 2025. Studies were eligible if they included at least ten iCCA patients receiving conversion or neoadjuvant systemic therapy and reported treatment outcomes. Aggregated data meta-analyses were performed for categorical outcomes and individual patient-data meta-analyses were performed to evaluate overall survival (OS).

Results: Twenty-one studies (13 conversion, 8 neoadjuvant) including a median of 45 patients per study [interquartile range (IQR) 23-77] were analyzed. In the conversion setting, the pooled secondary resectability rate was 23.7%. Median OS was 64.7 months after conversion surgery vs. 13.1 months after systemic therapy alone. In the neoadjuvant setting, the dropout risk exceeded 20%; however, when the entire treatment sequence was completed, preoperative therapy was associated with improved OS from diagnosis compared with upfront surgery [5-year OS: 44% vs. 37%; hazard ratio (HR) = 0.833, P < 0.001]. Pooled postoperative mortality and severe morbidity rates were 1.2% and 19.1%, with similar outcomes in conversion and neoadjuvant groups.

Conclusion: Systemic therapy is a key adjunct in iCCA management without compromising perioperative safety. Conversion therapy enables secondary resection with favorable long-term outcomes; neoadjuvant therapy in high-risk resectable patients improves postoperative survival but carries a non-negligible risk of treatment dropout.

Cancers doi: 10.20517/2394-5079.2025.57

Authors: Meng Li,Weihua Song,Yichi Wu,Haiping Lin,Wangrui Liu,Jiachang Chi

Hepatocellular carcinoma (HCC) arises in a cirrhotic, tolerogenic liver and within a heterogeneous tumor microenvironment (TME) that constrains the efficacy of single-agent systemic therapy. Although immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs have enhanced results, clinicians still lack a mechanistic framework to match specific combinations and locoregional therapies to distinct TME states or disease stages. Here, we synthesize late-phase clinical trial data and experimental studies to link three dominant TME phenotypes - inflamed, immune excluded and immune desert - to first-line ICI-based regimens, including atezolizumab-bevacizumab, durvalumab-tremelimumab, nivolumab-ipilimumab and tyrosine kinase inhibitor-ICI combinations. We outline how the vascular endothelial growth factor (VEGF)-immunity axis, immunogenic cell death after transarterial chemoembolization (TACE), ablation and radiotherapy, and cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING)-driven type I interferon signaling jointly rewire the TME and underpin the emerging “TACE-plus” standard (TACE + ICI + anti-VEGF therapy) in selected intermediate-stage HCC. We then integrate high response-rate regimens into practical algorithms for conversion and neoadjuvant therapy, cirrhosis-specific toxicity management and post-progression sequencing after ICI- or TACE-based treatment. Finally, we map next-generation approaches - Glypican-3-directed chimeric antigen receptor T-cell (CAR-T)/natural killer (NK)/tumor-infiltrating lymphocyte (TIL) products, novel checkpoints such as T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), STING agonists, and personalized neoantigen vaccines - onto putative TME states. We further highlight biomarker priorities, including β-catenin-mediated immune exclusion, angiogenic and interferon signatures, circulating tumor DNA and epigenetic readouts, and the gut-liver axis. A TME-anchored view of HCC provides a rational basis for integrating systemic and locoregional therapies, expanding curative opportunities and designing phenotype-enriched trials.

Cancers doi: 10.20517/2394-5079.2025.52

Authors: Diyu Chen,Guangming Xu,Aiqing Fan,Yichao Bu,Yuan Fang,Guiqi Zhu,Xiutao Fu,Weiren Liu,Zhenbin Ding,Jian Zhou,Jia Fan,Yinghong Shi,Zheng Tang

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.

Cancers doi: 10.20517/2394-5079.2025.42

Authors: Francesco Tovoli,Laura Crocetti,Chiara Mazzarelli,Francesco Giuseppe Foschi,Raffaella Tortora,Martina Gambato,Alessandro Vitale,

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.

Cancers doi: 10.20517/2394-5079.2025.106

Authors: Ben Brown,Wen Yuan Chung,John Isherwood

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.

Cancers doi: 10.20517/2394-5079.2025.39

Authors: Ludovico Abenavoli,Maria Luisa Gambardella,Eugenia Passante,Giuseppe La Torre,Caterina Battaglia,Francesco Manti,Domenico Console,Francesco Luzza,Domenico Laganà

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.

Cancers doi: 10.20517/2394-5079.2025.58

Authors: Zhao Ruan,Xuedan Sun

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.

Cancers doi: 10.20517/2394-5079.2025.58

Authors: Zhao Ruan,Xuedan Sun

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.

Cancers doi: 10.20517/2394-5079.2025.72

Authors: Ilaria Govoni,Virginia Padoan,Alessandro Vitale,Maria Rendina,Michele Finotti,Giovanni Battista Levi Sandri,Marco Brolese,

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.

Cancers doi: 10.20517/2394-5079.2025.92

Authors: Run-Ze Miao,Hao-Rui Zhu,Tian-Yi Li,Jian Zhou,Xin-Rong Yang

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.

Cancers doi: 10.20517/2394-5079.2025.75

Authors: Argyro Voumvouraki,Ioannis Tsomidis,Elias Kouroumalis

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.

Cancers doi: 10.20517/2394-5079.2025.81

Authors: Youzhi Lin,Meifang Pan,Di Tan,Ting Li,Yulei Lu,Hao Lai,Zongjia Wang,Xiaoli Liao

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.

Cancers doi: 10.20517/2394-5079.2025.102

Authors: Chunyi Zhu,Chuangye Han,Yongfei He,Shutian Mo,Youfang Wang,Jingren Shao,Tao Peng

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.

Cancers doi: 10.20517/2394-5079.2025.110

Authors: Chalv Fu,Licheng Wu,Chuanzhou Li

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.

Cancers doi: 10.20517/2394-5079.2025.74

Authors: Tingjiang He,Ludan Zhang,Qianwei Zhao

Hepatocellular carcinoma (HCC) is predominantly diagnosed at an advanced stage and ranks as the third leading cause of cancer-related mortality worldwide. In recent years, the advent and clinical application of immune checkpoint inhibitors (ICIs) have markedly transformed the therapeutic landscape of HCC, yielding superior overall survival (OS) outcomes compared with conventional targeted therapies. Nevertheless, clinical benefit is limited to a subset of patients, largely due to drug resistance. Current evidence implicates both the tumor microenvironment and tumor cell-intrinsic factors as pivotal determinants of ICI resistance. Combination strategies have emerged as a central approach in HCC therapy, significantly enhancing the antitumor activity of ICIs. Notably, ICIs plus targeted therapy (anti-angiogenic agents), dual-ICI blockade, and ICI combined with locoregional therapy (transarterial chemoembolization) currently represent the most well-established and clinically validated approaches, being approved as first- or second-line treatments. In addition, complementary approaches, including traditional Chinese medicine and modulation of intestinal microbiota, demonstrate synergistic antitumor effects when integrated with ICI, representing promising avenues for further therapeutic optimization. This review mainly elucidates the underlying mechanisms of ICI resistance and examines both established and emerging combination strategies for HCC. Furthermore, it explores potential approaches to enhance the efficacy of ICI-based regimens, with the aim of improving long-term outcomes for patients with advanced HCC.

Cancers doi: 10.20517/2394-5079.2025.118

Authors: Lu Han,Fei Song

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.

Cancers doi: 10.20517/2394-5079.2025.70

Authors: Bailey Hall,Zachary Ohs,Mario Dervishi,Alex Stevens,Christopher Sutter,Jon Davidson

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.

Cancers doi: 10.20517/2394-5079.2025.105

Authors: Yang Wang,Yi-Jun Lu,Jian Zhou,Xin-Rong Yang

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.

Cancers doi: 10.20517/2394-5079.2026.15

Authors: Sakktivel Elangovan,Chang Chuen Mark Cheah,George Boon-Bee Goh

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.

Cancers doi: 10.20517/2394-5079.2025.108

Authors: Zong Wu,Yixiu Wang,Qi Pan,Weiqi Xu,Lu Wang,Yongfa Zhang

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.

Cancers doi: 10.20517/2394-5079.2026.01

Authors: Qichao Fan,Yachun Chen,Junjin Liu,Liang Gao,Jiaofeng Huang

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.

Cancers doi: 10.20517/2394-5079.2026.03

Authors: Jie Wang,Runqiu Jiang

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.

Cancers doi: 10.20517/2394-5079.2026.13

Authors: Yu Chang,Jie Chen,Zhuang Zhang,Wanshui Yang

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.

Cancers doi: 10.20517/2394-5079.2025.77

Authors: Paolo De Simone,Daniela Peritore,Juri Ducci,Lucia Romano,Donato Longo,Antonio Giuliani,Daniela Campani,Fabio Vistoli

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].

Cancers doi: 10.20517/2394-5079.2026.09

Authors: Yichen Liu,Shu-Yu Liu,Wen-Yuan Chung,David Bowrey,Kai-Wen Huang

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.

Cancers doi: 10.20517/2394-5079.2026.04

Authors: Taishun Mao,Junqing Jiang,Ping Liu,Yongxiang Zhao,Liping Zhong,Zerui Zhang,Kaichun Wu,Limin Xia

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.

Cancers doi: 10.20517/2394-5079.2026.10

Authors: Shufen Xia,Qingxia Yang,Yuyao Liu,Aohui Yan,Shangru Li,Linfu Xu,Huayu Guan,Yubin Xie,Shixian Hu

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.

Cancers doi: 10.20517/2394-5079.2026.29

Authors: Jingyue Tan,Zixuan Xing,Jian Zu,Zhanpeng Yang,Yue Zhang,Xiao Yuan,Qiaoman Fei,Dou Qu,Chongyu Zhang,Yajing Bo,Zhiluo Yang,Xinyuan He,Meijuan Han,Fanpu Ji,Yujiao Deng,Yuan Wang

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.

Cancers doi: 10.20517/2394-5079.2026.19

Authors: Giacinta Ciancimino,Fabiana Pecorella,Silvia Maria Viscardi,Claudia La Mantia,Antonino Caserta,Grazia Pennisi,Salvatore Petta

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.

Cancers doi: 10.20517/2394-5079.2026.21

Authors: Eunho Choi,Young-Sun Lee,Dong Hyeon Lee,Won Kim,

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.

Cancers doi: 10.20517/2394-5079.2025.69

Authors: Man Kit Christopher Chu,Man Tong

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.