Background/Aims Lenvatinib resistance and immune exclusion limit outcomes in HCC. We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and PD-1 blockade.
Methods We established LS/LR HCC models and employed multi-omics (proteomics/RNA-seq), ChIP, luciferase, and RIP assays to map HKDC1 regulation. Tumor immunity was profiled by scRNA-seq, mIHC, and flow cytometry. SPD + lenvatinib efficacy was tested in cell lines, patient-derived organoids/xenografts. Tested therapy effect in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion; and analyzed a postoperative cohort (n = 40) treated with lenvatinib + PD-1.
Results HKDC1, upregulated in LR HCC, was transcriptionally activated by USF1 and promoted SMS-mediated polyamine rewiring. This impaired CD8⁺ T-cell metabolism, reversible by HKDC1 knockdown or spermidine (SPD). SPD synergized with lenvatinib, triggering autophagy and suppressing tumor growth in vitro and in vivo. High HKDC1 predicted poor response and survival in patients receiving lenvatinib + aPD-1.
Conclusions A USF1/HKDC1/SMS axis couples polyamine metabolism to immune dysfunction and lenvatinib resistance. HKDC1 is a predictive biomarker and therapeutic node and support polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer mortality worldwide. Its pathogenesis reflects a combination of tumour-intrinsic heterogeneity and a profoundly immunosuppressive tumour microenvironment. Growing evidence shows that tumours recapitulate developmental programs to establish an oncofetal ecosystem, characterised by the re-expression of foetal antigens and foetal-like stromal and immune subsets. These features drive immune evasion and shape therapeutic response, contributing to immunotherapy outcomes in clinic. This review outlines mechanistic insights into oncofetal reprogramming across tumour, stromal, and immune compartments and evaluates therapeutic strategies that target these dependencies. We highlight emerging vaccine platforms, cellular therapies, and biologics targeting oncofetal antigens, with particular emphasis on mRNA–lipid nanoparticle vaccines and their potential to induce robust, durable antitumour immunity. We further discuss rational combinatorial strategies that integrate vaccines with immune checkpoint inhibitors. Finally, we discuss how overcoming liver tolerance and antigenic heterogeneity will be essential for effective oncofetal-directed therapies. Collectively, targeting the oncofetal ecosystem through coordinated vaccine, cellular, and immunotherapeutic strategies offers a path toward more durable responses and broader immunotherapy benefits in HCC.
Background/Aims The GALAD (Gender, Age, Lens culinaris agglutinin-reactive alpha-fetoprotein [AFP-L3], alpha-fetoprotein [AFP], and des-γ-carboxy prothrombin [DCP]) score, widely used for hepatocellular carcinoma (HCC) detection, was primarily derived from cohorts with advanced-stage tumors and elevated biomarker levels, potentially overestimating accuracy in early-stage disease. Furthemore, the lectin-based AFP-L3 assay has poor sensitivity at low AFP concentrations, limiting detection of small or AFP-negative tumors.
Methods We developed GAFAD, a multivariable model replacing AFP-L3 with fucosylated AFP percentage (AFP-Fuc%), quantified by a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay. The model was trained and tested using a hepatitis B virus (HBV)-related cohort (HCC n=235; non-HCC n=290), a diagnostically challenging set with substantial overlap in biomarker levels between HCC and non-HCC. Moreover, a final model (GAFAD) was validated in two independent cohorts (HCC n=210, non-HCC n=245), comprising HBV-, HCV-related and non-viral etiologies.
Results In the development cohort, GAFAD showed superior diagnostic performance to GALAD for distinguishing HCC from non-HCC, with a higher area under the receiver operating characteristic curve (AUC, 0.938 vs. 0.887; p<0.0001) and greater sensitivity (82% vs. 66%) and accuracy (86% vs. 79%) at 90% specificity. In the external validation cohort, GAFAD similarly outperformed GALAD, achieving a higher AUC (0.874 vs. 0.841, p<0.05), greater sensitivity (72% vs. 57%), and improved accuracy (82% vs. 75%) at 90% specificity. This superiority extended to early-stage, very-early-stage, and AFP-negative HCC.
Conclusions GAFAD provides a reliable and generalizable tool for early HCC detection across diverse etiologies, supporting its clinical applicability in surveillance and diagnosis.
Background/Aims Liver transplantation (LT) following total hepatectomy is a life-saving treatment for hepatocellular carcinoma (HCC). The HCC recurrence after LT hinders the effectiveness of the procedure. The objective of this study is to develop a pre-operative risk stratification model based on a liquid biopsy.
Methods We conducted a comprehensive multi-omics study of 260 HCC patients from three centers, including clinical data, low-coverage whole-genome sequencing of cell-free DNA (cfDNA) from plasma, as well as whole-exome, single-nucleus RNA, and spatial transcriptomics from matched tumor and non-tumor tissues.
Results We identified cfDNA-derived copy number alteration (CNA) signatures associated with post-transplant recurrence. By integrating cfDNA-derived CNA profiles with single-cell transcriptomic data, we traced recurrence-associated cfDNA to a distinct subpopulation of malignant cells within the primary tumor. These cells were embedded in a pro-metastatic microenvironment of specialized endothelial subtypes and cancer-associated fibroblasts. Notably, most recurrence-associated lesions were detectable in cfDNA prior to liver transplantation (LT). Building on these insights, we developed the ZJU Criteria based on CNA fragments and tumor markers, a pre-LT risk prediction tool that integrates conventional clinical factors with cfDNA-derived CNA signatures, and validated it using internal and independent external cohorts.
Conclusion Our findings suggest that post-transplant recurrence commonly originates from advanced subclones that emerge late during tumor evolution. The ZJU Criteria provides an accurate, non-invasive strategy that significantly improves pre-LT risk stratification and clinical decision-making for patients with HCC.
Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver disease and hepatocellular carcinoma (HCC). Advances in surgical techniques and immunosuppressive regimens have markedly improved early post-transplant survival. However, long-term outcomes remain compromised by HCC recurrence, chronic rejection, metabolic complications, and de novo malignancies. Recurrence of HCC after LT remains a major clinical challenge, with available prognostic models providing limited accuracy in risk stratification. Simultaneously, systemic therapies for unresectable HCC have rapidly advanced, particularly with immune checkpoint inhibitors (ICIs), providing new opportunities and unique challenges in transplant settings. With ICIs carrying a risk of acute and potentially fatal rejection and lacking controlled data on efficacy or safety in the post-transplant setting, tyrosine kinase inhibitors currently represent a standard option for post-transplant recurrence. Novel biomarkers, such as donor-derived cell-free DNA and the gut microbiome, are emerging as potential tools to refine risk stratification and guide immunosuppression. Furthermore, innovative immunotherapies, including oncolytic viruses and mRNA vaccines, are being explored as tumor-specific approaches. Collectively, these advances may reshape future management of LT recipients.
Background/Aims Hepatocellular carcinoma (HCC) is characterized by profound transcriptomic dysregulation, yet the mechanism(s) by which DNA methylation is coordinated with chromatin modifications to regulate alternative splicing during tumorigenesis remains poorly understood.
Methods Using prospectively paired multi-omics data obtained from metabolic dysfunction-associated steatotic liver disease (MASLD)-HCC patients and coupled with a premalignant MASLD cohort, we have uncovered a previously unrecognized gene-regulatory axis centered on TACC3 isoform-switching.
Results In the non-tumoral context, the TACC3-201 isoform directly engages the histone acetyltransferase KAT2A to coordinate the regulation of NOTCH4 signaling. In HCC, this regulatory axis is disrupted whereby FOXM1 overrides DNMT1-mediated methylation, upregulating TACC3, and decoupling TACC3 from the KAT2A-associated NOTCH4 co-expression module. This rewiring is licensing tumor-specific cell-cycle progression and epigenetic plasticity. Thus, FOXM1 reshapes the TACC3-KAT2A interaction, while DNMT1 drives context-dependent DNA methylation, activating the CDK1-inhibitory kinase PKMYT1.
Conclusions We uncovered TACC3-KAT2A as an emerging regulatory axis caused by alternative splicing in HCC and propose FOXM1-driven TACC3 inhibition to synergistically disrupt mitotic fidelity and transcriptional regulation, potentially offering new therapeutic avenues for HCC with reduced toxicity to the normal liver.
Background/Aims Lenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood.
Methods Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort.
Results Resistant HCC exhibited significant enrichment of a COLEC12high TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models.
Conclusions Our work establishes the COLEC12high TAM/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.
Background/Aims Regorafenib is recommended by guidelines and trials as a sequential second-line therapy following progression on first-line sorafenib or lenvatinib in hepatocellular carcinoma (HCC). However, efficacy is limited, highlighting the urgent need to screen suitable patients and develop sensitization strategies.
Methods Acquired sorafenib- or lenvatinib-resistant (SR or LR) HCC cell lines and organoids were established. Genome-wide CRISPR library screen was performed in SR or LR cell strains to identify synthetic lethal targets of regorafenib. RNA-seq and FITC-regorafenib efflux assay were used to elucidate ERBB3-driven downstream signaling. Preclinical mouse models of cell line- and patient-derived xenografts and clinical cohorts of HCC patients were employed to validate the efficacy of ERBB3-guided patient stratification.
Results Screening with CRISPR library, we showed that inhibition of ERBB3 was synthetic lethal with regorafenib in SR or LR cell strains and organoids. Mechanistically, SR or LR triggered feedback activation of ERBB3 signaling and mediated regorafenib efflux via ERBB3-HIF1A-ABCB1 cascade pathway, limiting sensitivity to regorafenib. Moreover, ERBB3-low tumors following SR or LR exhibited significant sensitivity to regorafenib, suggesting its potential as a predictive biomarker to screen optimal candidates for sequential therapy. Seribantumab, an ERBB3-targeting monoclonal antibody, inhibited ERBB3-HIF1A-ABCB1 cascade, and its combination with regorafenib exerted marked synergistic anti-tumor effects on ERBB3-high tumors resistant to sorafenib or lenvatinib both in vitro and in vivo.
Conclusions This study revealed that ERBB3 was a key resistance factor driving limited efficacy to sequential regorafenib, but also an effective therapeutic target whose inhibition enhanced regorafenib sensitivity after SR or LR.
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Liver cancer is one of the deadliest malignancies, with increasing incidence worldwide. Recent advances in immunotherapy have expanded the options for systemic therapy against advanced hepatocellular carcinoma (HCC), but there are no biomarkers currently available to predict which patients will respond, leading to suboptimal patient selection strategies. Understanding of the genetic and immunologic features of HCC is accelerating rapidly through the use of single cell and spatial transcriptomic techniques. However, there is a need to translate insights gained through these new studies to improve treatment options and improve patient selection. In this review we summarize knowledge of the immunogenomics of HCC, emphasizing recent advances, and discuss progress toward clinical translation.
Xinrui Jin, Sherlot Juan Song, Jimmy Che-To Lai, Grace Lai-Hung Wong, Alice Pik-Shan Kong, Nana Peng, Xiang Xiao, Vincent Wai-Sun Wong, Terry Cheuk-Fung Yip
Clin Mol Hepatol 2026;32(1):353-367. Published online December 1, 2025
Background/Aims Previous studies suggest that hypothyroidism is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and its histological severity, but clinical outcome data are largely lacking. We aimed to study the impact of hypothyroidism on liver-related events (LREs).
Methods Patients with MASLD were identified from a territory-wide registry in Hong Kong during 2000–2024. Thyroid status was determined using diagnosis codes and thyroid function tests. The primary outcome, LRE, was defined as a composite of hepatic decompensation, hepatocellular carcinoma, liver transplantation, and liver-related death.
Results A total of 20,478 patients with MASLD were included in the final analysis (mean age 56.4±13.2 years; 43.9% male). At baseline, 18,178 (88.8%) patients were euthyroid, 598 (2.9%) were hyperthyroid, and 1,702 (8.3%) were hypothyroid. Compared with euthyroid patients, both hyperthyroidism and overt hypothyroidism were associated with cirrhosis. At a median follow-up of 4.8 years, 179 patients developed LREs, and 26 died from liver disease. Compared with patients with normal serum thyroid-stimulating hormone (TSH) levels of 0.4–4 mIU/L, those with subclinical (4–10 mIU/L; adjusted time-dependent cause-specific hazard ratio [aCSHR], 2.49; 95% CI, 1.51–4.13) and overt hypothyroidism (>10 mIU/L; aCSHR, 4.91; 95% CI, 1.56–15.47) had an increased risk of LREs. Time-dependent, but not baseline, TSH and thyroid status were associated with LRE risk.
Conclusions Subclinical and overt hypothyroidism are associated with an increased risk of LREs in a dose-dependent manner. The association with time-dependent but not baseline thyroid status underscores the importance of thyroid monitoring and suggests that correction of hypothyroidism may mitigate LRE risk.
Won Suk Lee, Seonjeong Woo, Sung Hwan Lee, Gae Hoon Jo, Ilhwan Kim, Hyeyeong Kim, Chansik An, Sanghoon Jung, Gwangil Kim, Haeyoun Kang, Beodeul Kang, Jung Sun Kim, Ho Yeong Lim, Incheon Kang, Hannah Yang, So Jung Kong, Dahyeon Son, Dong Jun Shin, Woo Young Kwon, Da-Yeon Lee, Ju-Seog Lee, Junho Park, Youngsoo Kim, Sohyun Hwang, Chan Kim, Hong Jae Chon
Clin Mol Hepatol 2026;32(1):258-275. Published online October 27, 2025
Background/Aims Hepatocellular carcinoma (HCC) exhibits substantial morphological and biological heterogeneity. Clinical and molecular relevance of the infiltrative subtype remains poorly defined in the context of cancer immunotherapy. We aimed to evaluate the prognostic impact and molecular features of infiltrative HCC in patients treated with first-line atezolizumab plus bevacizumab (Ate/Bev).
Methods We included 307 patients with advanced HCC treated with Ate/Bev and classified them into four gross morphological types based on imaging. Multi-omics profiling was conducted on tumor samples. Type IV infiltrative signature was derived and externally validated using five independent HCC cohorts, including IMbrave150.
Results Infiltrative morphology, encompassing pure and mixed forms, was present in 42.7% of advanced HCC and associated with advanced disease features and compromised liver function. Patients with type IV infiltrative HCC showed lowest objective response rate (14.6%) and worst progression-free (median, 2.8 months) and overall survival (median, 7.1 months). Infiltrative morphology remained an independent predictor of poor outcomes after multivariable adjustment for confounders, including intrahepatic tumor extent. Genomic profiling revealed enriched TP53 and ATM loss-of-function mutations in type IV infiltrative HCC. Transcriptomic and proteomic analyses identified consistent activation of tumor proliferation, epithelial-mesenchymal transition, TGF-β signaling, and immunosuppressive pathways in type IV infiltrative HCC. Type IV infiltrative signature was significantly associated with poor survival across external datasets and retained independent prognostic value.
Conclusions Infiltrative HCC is a clinically aggressive and molecularly distinct subtype of advanced HCC. Morphological classification and type IV infiltrative signatures may guide risk stratification and therapeutic decision-making in advanced HCC treated with immunotherapy.
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Hepatocellular carcinoma (HCC) is the most common primary liver cancer and remains a major cause of cancer-related mortality worldwide. Systemic therapies, including targeted therapies and immune checkpoint inhibitors, have revolutionized the management of advanced HCC. Although the prognosis of patients with advanced HCC remains poor, significant progress has been made with recent advances in drug development, particularly with the introduction of effective treatments such as atezolizumab plus bevacizumab or durvalumab plus tremelimumab. Indeed, treatment response varies significantly among patients, highlighting the need for robust biomarkers. In addition, the development of molecular driver-targeted therapies remains an active research focus as most genetic alterations observed in HCC are currently undruggable. Meeting these goals will require additional efforts to obtain histological material in clinical trials, in order to enable robust translational research. This review explores the current landscape of biomarkers of response to systemic treatments in HCC, including molecular, immune-based markers as well as circulating tumor DNA and highlights potential paths of improvement.
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Intermediate-stage hepatocellular carcinoma (HCC) encompasses a diverse patient population that requires individualized treatment strategies and a multidisciplinary approach. Recent advancements in systemic therapy have expanded the therapeutic options for intermediate-stage HCC, allowing for combination strategies such as systemic therapy with transarterial chemoembolization (TACE) and upfront systemic therapy for individuals deemed unsuitable for TACE. Additionally, the ongoing development of treatment modalities for intermediate-stage HCC has improved the potential for curative conversion and tumor downstaging. Nevertheless, consensus on the optimal management of intermediate-stage HCC remains limited. Thus, the primary aim of this study was to develop a set of consensus guidelines for the management of intermediate-stage HCC. To address this gap, the Taiwan Liver Cancer Association (TLCA) established a working group to develop a multidisciplinary strategy for managing intermediate-stage HCC. Here, we present eight consensus statements formulated by this expert panel, which outline criteria for TACE unsuitability, treatment recommendations based on TACE eligibility, and considerations for various modalities, including conventional TACE, drug-eluting bead TACE, and transarterial radioembolization, as well as the appropriate timing for initiating systemic therapy to enable curative conversion and downstaging. These statements provide specific, evidence-based recommendations for clinicians, addressing treatment pathways based on TACE eligibility and other key considerations for intermediate-stage HCC management. The development of this consensus guideline is intended to aid clinicians in selecting the most appropriate treatment pathway for intermediate-stage HCC, support personalized treatment planning, and ultimately enhance the feasibility of achieving curative conversion.
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Through the implementation of hepatitis B vaccination and effective antiviral treatment over the past four decades, the hepatitis B surface antigen (HBsAg) seroprevalence of the vaccinated generation dramatically decline. The incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) also decreases. However, the elimination of HBV is still a challenge to achieve. Novel HBV biomarkers, including quantitative HBsAg, hepatitis B virus core-related antigen and HBV RNA are promising in predicting clinical phases, risks of disease progression and HBV functional cure. Current antiviral therapies, nucleoside/nucleotide and pegylated alpha-interferon, effectively decrease HCC incidence in chronic hepatitis B (CHB) patients and minimize the recurrence of HCC in patients receiving curative therapy. Novel agents under development to achieve HBV cure include direct-acting antivirals that target various stages of the HBV lifecycle and host targeting agents that enhance HBV-specific immunity. The action plans for eliminating hepatitis B in the future are universal HBV screening, early and simplified treatment as well as precision lifelong management for CHB patients. This narrative review will summarize and discuss global strategies and initiatives aimed at eliminating HBV infection.
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Background/Aims Hepatocellular carcinoma (HCC) frequently recurs after curative treatment, posing challenges to long-term survival. Although contrast-enhanced multiphasic computed tomography (CECT) is commonly used for detecting recurrence, it is associated with risks such as radiation exposure and contrast agent reactions. This study aimed to compare the diagnostic performance of non-contrast magnetic resonance imaging (NC-MRI) with CECT for detecting recurrent HCC.
Methods In this prospective multicenter intra-individual head-to-head comparison trial (study identifier: NCT05690451, KCT0006395), participants who had undergone curative treatment for HCC and remained recurrence-free for over two years were enrolled. Each participant underwent three follow-up imaging sessions at 2–6-month intervals using both CECT and NC-MRI. The primary outcome was the detection accuracy of each modality, analyzed using the generalized estimating equation analysis. Secondary outcomes included sensitivity and specificity.
Results The study included 203 participants with a total of 528 paired imaging sessions, identifying recurrent HCC in 22 cases (10.8%). Among these, 21 cases involved intrahepatic recurrence with a median tumor size of 1.3 cm, and one case had aortocaval lymph node metastasis. NC-MRI achieved a detection accuracy of 96.6% (196/203), higher than CECT’s 91.6% (186/203) (P=0.006). NC-MRI also showed greater sensitivity (77.3% [17/22] vs. 36.4% [8/22]; P=0.012), while specificity was comparable between NC-MRI and CECT (98.9% [179/181] vs. 98.3% [178/181]; P=0.999).
Conclusions NC-MRI demonstrated higher sensitivity and accuracy compared to CECT in detecting recurrent HCC in patients who had been disease-free for over two years following curative treatment, indicating its potential as a preferred imaging modality for this purpose.
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Background/Aims Hepatitis C virus (HCV) infection remains a global health challenge, leading to chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Despite the high efficacy of direct-acting antiviral therapy in achieving sustained virologic response (SVR), concerns persist regarding long-term immune alterations and residual risks, particularly in cirrhotic patients.
Methods This study investigates 75 soluble immune mediator (SIM) profiles in 102 chronic HCV patients, stratified by cirrhosis status, at therapy initiation, end of treatment, and long-term follow-up (median 96 weeks). Findings were compared with 51 matched healthy controls and validated in an independent cohort of 47 cirrhotic patients, 17 of whom developed HCC.
Results We observed significant SIM alterations at baseline, with cirrhotic patients displaying a more profoundly dysregulated inflammatory milieu. Despite an overall decline in inflammatory markers following SVR, persistent alterations were evident, particularly in cirrhotic patients. Notably, those with liver stiffness exceeding 14 kPa exhibited sustained inflammatory dysregulation, correlating with liver elastography values. Key SIM such as interleukin (IL)-6, IL-8, urokinase plasminogen activator, and hepatocellular growth factor remained elevated and were associated with HCC development. Network analysis highlighted their roles in liver fibrosis, regeneration, and carcinogenesis.
Conclusions These findings underscore the importance of early antiviral intervention to prevent cirrhosis-related sequelae. Future studies should explore the mechanistic pathways linking chronic inflammation, fibrosis, and oncogenesis to identify predictive biomarkers and novel therapeutic targets. Addressing persistent immune alterations post-HCV clearance may improve long-term outcomes, particularly in patients with advanced liver disease.
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