Clinical and Molecular Hepatology

"Immunotherapy"

Correspondence

Correspondence to letter to the editor on “Integrative multi-omics profiling identifies infiltrative hepatocellular carcinoma as an immunotherapy-resistant subtype with distinct molecular features”: Won Suk Lee, Seonjeong Woo, Sohyun Hwang, Chan Kim, Hong Jae Chon; Clin Mol Hepatol 2026;32(3):e411-e414.
Published online July 1, 2026; DOI: https://doi.org/10.3350/cmh.2026.0208

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Original Articles

Inactivating LATS2 variation drives tumor progression and resistance to anti-PD-1 therapy in intrahepatic cholangiocarcinoma: Ye Xu, Kai-Xuan Liu, Xin-Yu Wang, Shuang-Yi Chen, Yu-Hang Ye, Ning Li, Fan Weng, Long Chen, Cun-Yang Tu, Zi-Han Tian, Chu-Bin Luo, Zhi-Qiang Hu, Zheng-Jun Zhou, Jia Fan, Jian Zhou, Shao-Lai Zhou; Clin Mol Hepatol 2026;32(3):1288-1304.
Published online March 18, 2026; DOI: https://doi.org/10.3350/cmh.2025.0997

Abstract
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Background/Aims
Recurrence is a major factor limiting the long-term survival of patients with intrahepatic cholangiocarcinoma (ICC). The molecular characteristics and potential therapeutic targets in ICC remain largely undefined.
Methods
Following our previous whole-exome sequencing study, we performed targeted sequencing, Sanger sequencing, and quantitative PCR to assess all coding exons and copy number variations of LATS2 in 400 primary ICC samples. Kaplan–Meier survival curves were used to assess the impact of LATS2 mutation, copy number loss, and low expression levels on recurrence-free survival and overall survival in ICC patients. In addition, we investigated the functional role and underlying mechanisms of LATS2 variation in ICC tumor progression and resistance to anti-PD-1 therapy.
Results
Among a total of 400 ICC cases, the overall frequencies of LATS2 somatic mutation and copy number loss were 3% (12/400) and 34% (136/400), respectively. Both types of variation were correlated with decreased LATS2 protein expression, increased tumor recurrence, and poor overall survival. Biofunctional investigations revealed a tumor-suppressor role of LATS2. Inactivation of LATS2 suppressed the Hippo signaling pathway, leading to aberrant activation of YAP, which upregulated PD-L1 expression and CCL2 secretion, suppressed CD8⁺ T cell infiltration, and enhanced recruitment of M2-like macrophages, thereby promoting immune evasion, tumor progression, and resistance to anti-PD-1 therapy.
Conclusions
Our study reveals a pivotal clinical association and mechanistic role of LATS2-inactivating variation in ICC, which may serve as a useful biomarker for precision therapy.

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HKDC1-mediated polyamine rewiring drives lenvatinib resistance and immune escape in hepatocellular carcinoma: Shiping Chen, Biao Wang, Yang Zhang, Bing Quan, Yujie Shao, Guiqi Zhu, Jialiang Cai, Peiling Zhang, Lina Song, Jinglei Wan, Yi Yang, Junxian Du, Yufan Cai, Zhi Dai; Clin Mol Hepatol 2026;32(3):1261-1287.
Published online March 11, 2026; DOI: https://doi.org/10.3350/cmh.2025.1269

Abstract
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Background/Aims
Lenvatinib resistance and immune exclusion limit outcomes in hepatocellular carcinoma (HCC). We hypothesized that metabolic rewiring orchestrates resistance to lenvatinib and programmed cell death protein 1 (PD-1) blockade.
Methods
We established lenvatinib-sensitive/lenvatinib-resistant (LS/LR) HCC models and employed multi-omics (proteomics/RNA-seq), chromatin immunoprecipitation, luciferase, and RNA immunoprecipitation assays to map hexokinase domain containing protein 1 (HKDC1) regulation. Tumor immunity was profiled by scRNA-seq, multiplex fluorescent immunohistochemistry, and flow cytometry. Spermidine (SPD)+lenvatinib efficacy was tested in cell lines and patient-derived organoids/xenografts. Therapeutic effects were tested in an immunocompetent hydrodynamic HCC model with hepatocyte-specific Hkdc1 deletion and were analyzed a postoperative cohort (n=40) treated with lenvatinib+PD-1.
Results
HKDC1, upregulated in LR HCC, was transcriptionally activated by upstream stimulatory factor 1 (USF1) and promoted spermine synthase (SMS)-mediated polyamine rewiring. This impaired CD8⁺ T-cell metabolism, reversible by HKDC1 knockdown or 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 supports polyamine-axis modulation to sensitize HCC to lenvatinib plus PD-1 therapy.

Citations

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Regulation of immune tolerance in hepatocellular carcinoma by liver diseases: a review
Jinyi Li, Yuanda Liu
Infectious Agents and Cancer.2026;[Epub] CrossRef

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Crossref

Review

Oncofetal reprogramming in hepatocellular carcinoma: linking developmental programs to cancer vaccines and immunotherapy: Dayangku Nordiyana B. P. Hassanel, Ankur Sharma; Clin Mol Hepatol 2026;32(2):620-645.
Published online March 4, 2026; DOI: https://doi.org/10.3350/cmh.2025.1410

Abstract
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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.

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Letters to the Editor

Infiltrative hepatocellular carcinoma resistance: Integrating microenvironment, host factors, and therapy: Glenn Deng, Dating Han, Kejun Yan; Clin Mol Hepatol 2026;32(3):e288-e290.
Published online February 2, 2026; DOI: https://doi.org/10.3350/cmh.2026.0045

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From immune reshaping to functional cure: Translational considerations for natural killer cell therapy in hepatitis B virus: Letter to the editor on “Dissecting antibody-mediated natural killer cell effects reveals a cytotoxic CX3CR1⁺KLRC2^-CD16^hi subset linked to hepatitis B virus outcomes”: Long Xu, Yan Wang, Guiqiang Wang; Clin Mol Hepatol 2026;32(3):e312-e314.
Published online January 14, 2026; DOI: https://doi.org/10.3350/cmh.2025.1463

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Beyond the single model: Critical considerations for translating HCC triplet immunotherapy from bench to bedside: Letter to the editor on “Distinct tumor immune microenvironment modulation by anti-PD-1/PD-L1, VEGF, and CTLA-4 blockade provides a rationale for triplet therapy in hepatocellular carcinoma”: Han Zhuo, Yue Teng, Zhongming Tan; Clin Mol Hepatol 2026;32(3):e306-e308.
Published online December 26, 2025; DOI: https://doi.org/10.3350/cmh.2025.1398

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Original Article

Integrative multi-omics profiling identifies infiltrative hepatocellular carcinoma as an immunotherapy-resistant subtype with distinct molecular features: 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; DOI: https://doi.org/10.3350/cmh.2025.0792

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.

Citations

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Response: Reassessing the Use of Nivolumab Plus Ipilimumab After Atezolizumab Plus Bevacizumab in Advanced HCC
Jung Sun Kim, Thomas Yau, Hong Jae Chon
Liver International.2026;[Epub] CrossRef
Current and Emerging Immunotherapy Strategies in Hepatocellular Carcinoma: Standard Treatments and Biomarkers
Yoonseok Lee
Journal of Digestive Cancer Research.2026; 14(1): 53. CrossRef
Functional Interpretation of Recurrent Genetic Variants in Hepatocellular Carcinoma: Molecular Consequences and Clinical Relevance
Yuntao Ye, Zhulin Xu, Jiang Wang, Chunyu Chen, Yuan Peng, Bo Li, Shaoqiu Chen
Human Mutation.2026;[Epub] CrossRef
Efficacy of Nivolumab plus Ipilimumab in Advanced Hepatocellular Carcinoma with and without High-Risk Features: An International Multicenter Study
Jung Sun Kim, San-Chi Chen, Jeffrey Sum Lung Wong, Beodeul Kang, Ho Yeong Lim, Ilhwan Kim, Hyeyeong Kim, Chansik An, Su Jin Jang, Masatoshi Kudo, David Tai, Chan Kim, Thomas Yau, Hong Jae Chon
Liver Cancer.2026; : 1. CrossRef
Cancer Heterogeneity and Cancer Cell Plasticity: Molecular Mechanisms and Precision Therapy
Hanwen Hu, Zhixing Hao, Lili Li, Huiying Liu, Chenghui Yang, Zhen Wang
MedComm.2026;[Epub] CrossRef
Prognostic Significance of Glypican-3 Expression in Hepatocellular Carcinoma Treated with Atezolizumab-Bevacizumab
Ji Hoon Kim, Ji Won Han, Hee Sun Cho, Jeong Won Jang, Kwon Yong Tak, Pil Soo Sung
Cancers.2025; 17(24): 3967. CrossRef

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Reviews

Stratifying cholangiocarcinoma: tumor microenvironment, molecular drivers, and novel immunotherapeutic approaches: Cindy Xinqi Liu, Carmen Chak-Lui Wong; Clin Mol Hepatol 2026;32(1):127-155.
Published online October 14, 2025; DOI: https://doi.org/10.3350/cmh.2025.0889

Abstract
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Cholangiocarcinoma (CCA) is an epithelial cell cancer of the biliary tract. CCA can be further classified into intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), and distal cholangiocarcinoma (dCCA) depending on the anatomical location. Until recently, the treatment for advanced CCA has remained highly reliant on chemotherapy, with gemcitabine plus cisplatin used in first-line treatment. Recent developments have led to the addition of immune checkpoint blockade (ICB) to the chemotherapy regimen, highlighting the promising potential of immunotherapies for CCA treatment. Despite these developments, most patients still do not benefit from current treatments, and response rates to ICB monotherapy remain modest. This underscores the need to develop more effective immunotherapeutic strategies. A major obstacle to this is the highly heterogenous nature of the disease. CCA tumors exhibit high inter-tumor heterogeneity in terms of anatomical locations, driver mutations, etiologies, and tumor microenvironment (TME) composition, making each patient immunologically distinct and difficult to benefit from a one-size-fits-all approach. There is a need to stratify patients according to individual disease status to identify immunotherapies and combination therapies that are most beneficial to them. Here we describe the different ways inter-tumor heterogeneity may arise in CCA, including stromal cell abundance, anatomical location, driver mutations, etiologies, TME profile, and tertiary lymphoid structure (TLS) presence. We also discuss what these factors mean to the immune microenvironment and their potential to be used as biomarkers. Careful stratification of patients is crucial in designing personalized medicine to improve survival outcomes and treatment efficacy for CCA patients.

Citations

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Integrative single-cell and machine-learning analysis identifies ac4C-related S100A13 as a causal risk gene in cholangiocarcinoma
Yi Zheng, Yan Lin, Zilin Wang, Fazong Wu
BMC Cancer.2026;[Epub] CrossRef
Development of a prediction model integrating cardiac ultrasound parameters for cardiac complications after distal cholangiocarcinoma surgery: a retrospective cohort study
Fangfei Wang, Shan Jin, Shaocheng Lyu, Xin Zhao, Xiuzhang Lyu, Qiang He
BMC Medical Imaging.2026;[Epub] CrossRef
Combined Model of Inflammatory-Nutritional Indicators and Tumor Markers for Predicting Prognosis in Patients with Distal Cholangiocarcinoma: A Retrospective Cohort Study
Fangfei Wang, Jinhao Li, Xin Zhao, Shaocheng Lyu, Qiang He
Diseases.2026; 14(3): 97. CrossRef
A pyroptosis-related molecular signature stratifies prognosis and highlights GSDMB-mediated malignancy in intrahepatic cholangiocarcinoma
Binhan Zhao, Yongji Zhu, Ziyang Jin, Xiang Li, Kainan Lin, Yifan Wang, Yunkun Lu, Wen Hua
Biology Direct.2026;[Epub] CrossRef
Multidimensional Regulatory Networks of Immune Resistance in Intrahepatic Cholangiocarcinoma: Synergistic Mechanisms of Tumor Microenvironment, Immune Cells, and Microbiota, and Novel Therapeutic Strategies
Lingyu Kong, Hongxin Piao
Gastrointestinal Disorders.2026; 8(3): 32. CrossRef
CircUBAP2 promotes intrahepatic cholangiocarcinoma progression via PRMT1–p65 methylation and the miR-642b-5p/IL-1β axis
Chang Li, Shuochen Liu, Changan Chen, Kai Cao, Ruixiang Chen, Xiao Xu, Jiang Chang, Yaodong Zhang, Changxian Li, Xiangcheng Li
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2026; 1872(7): 168337. CrossRef

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Taiwan liver cancer association management consensus guidelines for intermediate-stage hepatocellular carcinoma: I-Cheng Lee, Hung-Wei Wang, Wei Teng, Tsung-Jung Lin, Chien-Hung Chen, Hsueh-Chou Lai, Teng-Yu Lee, Ching-Wei Chang, Chao-Hung Hung, Chia-Yen Dai, Yi-Ping Hung, Ying-Chun Shen, Chien-Wei Su, Ming-Chih Ho, Wei-Chen Lee, Gar-Yang Chau, Chin-Tsung Ting, Po-Chin Liang, Chien-An Liu, Pi-Yi Chang, Kuan-Yang Chen, Shi-Ming Lin, Li-Tzong Chen, Yi-Hsiang Huang, TLCA Intermediate Stage HCC Working Group; Clin Mol Hepatol 2025;31(4):1213-1232.
Published online August 4, 2025; DOI: https://doi.org/10.3350/cmh.2025.0724

Abstract
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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.

Citations

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Editorial: Tumour Burden Score and Extrahepatic Progression After TACE—Refining Risk Stratification Beyond the Liver
Chien‐Wei Su
Alimentary Pharmacology & Therapeutics.2026; 63(9): 1316. CrossRef
Optimal treatment selection for hepatocellular carcinoma in the era of immunotherapy
Chen-Ta Chi, Yi-Hsiang Huang
Journal of Gastroenterology.2026;[Epub] CrossRef
Patterns and Prognostic Stratification of Recurrence after Thermal Ablation in Patients with Hepatocellular Carcinoma
Chi-Ping Tan, Teng-Yu Lee, I-Cheng Lee, Kuo-Cheng Wu, Chien-An Liu, Nai-Chi Chiu, Shao-Jung Hsu, Pei-Chang Lee, Chi-Jung Wu, Chen-Ta Chi, Jiing-Chyuan Luo, Ming-Chih Hou, Yi-Hsiang Huang
Liver Cancer.2025; : 1. CrossRef

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Letter to the Editor

Molecular stratification of hepatocellular carcinoma by metabolic-signaling pathways guides precision immunotherapy and TACE therapy: Binghua Li, Yanchao Xu, Yican Zhu, Yukun Zhang, Zijie Wu, Tianci Luo, Laizhu Zhang, Weiwei Hu, Decai Yu; Clin Mol Hepatol 2026;32(1):e16-e20.
Published online May 8, 2025; DOI: https://doi.org/10.3350/cmh.2025.0344

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The survival prognosis after adjuvant transcatheter arterial chemoembolization in primary liver cancer: Aretrospective study
Zhangjun Chen, Chang Lin, Jie Zhang
Current Problems in Surgery.2025; : 101811. CrossRef
S100A9 promotes resistance to anti-PD-1 immunotherapy in hepatocellular carcinoma by degrading PARP1 and activating the STAT3/PD-L1 pathway
Xianwei Zhou, Chu Qiao, Xuehui Chu, Yajing Yang, Haoran Man, Jingxin Liu, Yunzheng Li, Zhu Xu, Huan Li, Xiaodong Shan, Zaowu Lian, Yanjun Lu, Weihong Wang, Decai Yu, Xitai Sun, Binghua Li
Cellular Oncology.2025; 48(5): 1433. CrossRef

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Editorial

Hepatic neoplasm

TM4SF1 - A new immune target for treatment of hepatocellular carcinoma: Editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma”: Chen Rui Yuan, Terence Kin Wah Lee; Clin Mol Hepatol 2025;31(2):646-649.
Published online February 10, 2025; DOI: https://doi.org/10.3350/cmh.2025.0102

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Correspondence

Hepatic neoplasm

Correspondence to editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma”: Weifeng Zeng, Furong Liu, Yachong Liu, Zhanguo Zhang; Clin Mol Hepatol 2025;31(2):e197-e199.
Published online February 5, 2025; DOI: https://doi.org/10.3350/cmh.2025.0085

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Editorial

Hepatic neoplasm

Targeting TM4SF1 to overcome immunotherapy resistance in hepatocellular carcinoma: Editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma”: Valerie Chew; Clin Mol Hepatol 2025;31(2):642-645.
Published online January 16, 2025; DOI: https://doi.org/10.3350/cmh.2025.0031

Citations

Citations to this article as recorded by

Correspondence to editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma”
Weifeng Zeng, Furong Liu, Yachong Liu, Zhanguo Zhang
Clinical and Molecular Hepatology.2025; 31(2): e197. CrossRef

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1 Web of Science
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Original Article

Hepatic neoplasm

Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma: Weifeng Zeng, Furong Liu, Yachong Liu, Ze Zhang, Haofan Hu, Shangwu Ning, Hongwei Zhang, Xiaoping Chen, Zhibin Liao, Zhanguo Zhang; Clin Mol Hepatol 2025;31(2):489-508.
Published online December 30, 2024; DOI: https://doi.org/10.3350/cmh.2024.0934

Background/Aims
Transmembrane 4 L six family member 1 (TM4SF1) is highly expressed and contributes to the progression of various malignancies. However, how it modulates hepatocellular carcinoma (HCC) progression and senescence remains to be elucidated.
Methods
TM4SF1 expression in HCC samples was evaluated using immunohistochemistry and flow cytometry. Cellular senescence was assessed through SA-β-gal activity assays and Western blot analysis. TM4SF1-related protein interactions were investigated using immunoprecipitation-mass spectrometry, co-immunoprecipitation, bimolecular fluorescence complementation, and immunofluorescence. Tumor-infiltrating immune cells were analyzed by flow cytometry. The HCC mouse model was established via hydrodynamic tail vein injection.
Results
TM4SF1 was highly expressed in human HCC samples and murine models. Knockdown of TM4SF1 suppressed HCC proliferation both in vitro and in vivo, inducing non-secretory senescence through upregulation of p16 and p21. TM4SF1 enhanced the interaction between AKT1 and PDPK1, thereby promoting AKT phosphorylation, which subsequently downregulated p16 and p21. Meanwhile, TM4SF1-mediated AKT phosphorylation enhanced PD-L1 expression while reducing major histocompatibility complex class I level on tumor cells, leading to impaired cytotoxic function of CD8+ T cells and an increased proportion of exhausted CD8+ T cells. In clinical HCC samples, elevated TM4SF1 expression was associated with resistance to anti-PD-1 immunotherapy. Targeting TM4SF1 via adeno-associated virus induced tumor senescence, reduced tumor burden and synergistically enhanced the efficacy of anti-PD-1 therapy.
Conclusions
Our results revealed that TM4SF1 regulated tumor cell senescence and immune evasion through the AKT pathway, highlighting its potential as a therapeutic target in HCC, particularly in combination with first-line immunotherapy.

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Ana Beathriz Leite Lorente, Sergio Vazquez, Kanako Iwasaki, Adedoyin Adebayo, Maya Jackson, Christopher Cahill, Summer Ryan, Brooke A. Sullivan, Susan Bonner-Weir, Cristina Aguayo-Mazzucato
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Bowei Liu, Zhigang Peng, Hao Zhang, Nan Zhang, Zaoqu Liu, Zhiwei Xia, Shaorong Huang, Peng Luo, Quan Cheng
Molecular Cancer.2025;[Epub] CrossRef
TM4SF1 - A new immune target for treatment of hepatocellular carcinoma: Editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma”
Chen Rui Yuan, Terence Kin Wah Lee
Clinical and Molecular Hepatology.2025; 31(2): 646. CrossRef
Targeting TM4SF1 to overcome immunotherapy resistance in hepatocellular carcinoma: Editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma”
Valerie Chew
Clinical and Molecular Hepatology.2025; 31(2): 642. CrossRef
Correspondence to editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma”
Weifeng Zeng, Furong Liu, Yachong Liu, Zhanguo Zhang
Clinical and Molecular Hepatology.2025; 31(2): e197. CrossRef
Tetraspan(in)-mediated immune regulation in hepatocellular carcinoma: Editorial on “Targeting TM4SF1 promotes tumor senescence enhancing CD8+ T cell cytotoxic function in hepatocellular carcinoma”
Seo Hee Jin, Dong Joo Kim, Jung Weon Lee
Clinical and Molecular Hepatology.2025; 31(2): 650. CrossRef
Differential Infiltration of T-Cell Populations in Tumor and Liver Tissues Predicts Recurrence-Free Survival in Surgically Resected Hepatocellular Carcinoma
Eun Ji Jang, Ho Joong Choi, Young Kyoung You, Deok Hwa Seo, Mi Hyun Kwon, Keungmo Yang, Jaejun Lee, Jeong Won Jang, Seung Kew Yoon, Ji Won Han, Pil Soo Sung
Cancers.2025; 17(9): 1548. CrossRef
Immunoregulatory mechanisms in the aging microenvironment: Targeting the senescence-associated secretory phenotype for cancer immunotherapy
Haojun Wang, Yang Yu, Runze Li, Huiru Zhang, Zhe-sheng Chen, Changgang Sun, Jing Zhuang
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Targeting tumor-associated macrophages to overcome immune checkpoint inhibitor resistance in hepatocellular carcinoma
Fen Liu, Xianying Li, Yiming Zhang, Shan Ge, Zhan Shi, Qingbin Liu, Shulong Jiang
Journal of Experimental & Clinical Cancer Research.2025;[Epub] CrossRef
The role of PD‑1/PD‑L1 axis in liver diseases
Zijian Zeng, Shuanglan Chen, Qun Niu, Haijian Dong, Yuanqian Yao, Kaixin Wang, Xueqing Gong, Hui Li
Clinical and Experimental Medicine.2025;[Epub] CrossRef

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Reply to Correspondence

Hepatic neoplasm

Reply to correspondence on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”: Hiroaki Kanzaki, Yujin Hoshida; Clin Mol Hepatol 2025;31(1):e121-e122.
Published online October 11, 2024; DOI: https://doi.org/10.3350/cmh.2024.0886

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Correspondences

Hepatic neoplasm

Correspondence to editorial 2 on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 trial”: Sun Young Yim, Sung Hwan Lee, Ji Hoon Kim, Sunyoung S Lee, Ahmed O Kaseb, Ju-Seog Lee; Clin Mol Hepatol 2025;31(1):e84-e86.
Published online October 7, 2024; DOI: https://doi.org/10.3350/cmh.2024.0830

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51 Download

Hepatic neoplasm

Correspondence to editorial 1 on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 Trial”: Sung Hwan Lee, Sun Young Yim, Ji Hoon Kim, Sunyoung S. Lee, Ahmed O. Kaseb, Ju-Seog Lee; Clin Mol Hepatol 2025;31(1):e81-e83.
Published online October 7, 2024; DOI: https://doi.org/10.3350/cmh.2024.0829

Citations

Citations to this article as recorded by

Reply to correspondence on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”
Hiroaki Kanzaki, Yujin Hoshida
Clinical and Molecular Hepatology.2025; 31(1): e121. CrossRef

6,020 View
48 Download
Crossref

Hepatic neoplasm

Correspondence to letter to the editor on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”: Sung Hwan Lee, Sun Young Yim, Ji Hoon Kim, Sunyoung S Lee, Ahmed O Kaseb, Peng Wei, Ju-Seog Lee; Clin Mol Hepatol 2025;31(1):e110-e112.
Published online October 2, 2024; DOI: https://doi.org/10.3350/cmh.2024.0828

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59 Download

Letter to the Editor

Hepatic neoplasm

Comprehensive analysis of transcriptomic biomarkers for predicting response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Binghua Li, Jingyuan Wen, Zhu Xu, Peng Yan, Bing Han, Decai Yu; Clin Mol Hepatol 2025;31(1):e31-e34.
Published online September 20, 2024; DOI: https://doi.org/10.3350/cmh.2024.0628

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Intratumoral Proton Density Fat Fraction Predicts the Outcome of HAIC Combined With PD‐1 Inhibitors in Advanced Hepatocellular Carcinoma
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S100A9 promotes resistance to anti-PD-1 immunotherapy in hepatocellular carcinoma by degrading PARP1 and activating the STAT3/PD-L1 pathway
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iLIVER.2024; 3(4): 100130. CrossRef

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Editorial

Hepatic neoplasm

Transcriptomic signature in advanced hepatocellular carcinoma tissue to predict combination immunotherapy response: Editorial on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”: Hiroaki Kanzaki, Yujin Hoshida; Clin Mol Hepatol 2025;31(1):308-310.
Published online August 30, 2024; DOI: https://doi.org/10.3350/cmh.2024.0726

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Correspondence to editorial 1 on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 Trial”
Sung Hwan Lee, Sun Young Yim, Ji Hoon Kim, Sunyoung S. Lee, Ahmed O. Kaseb, Ju-Seog Lee
Clinical and Molecular Hepatology.2025; 31(1): e81. CrossRef
Advances and challenges in immunotherapy and molecular imaging for hepatocellular carcinoma
Tu Haibin
Discover Oncology.2025;[Epub] CrossRef

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104 Download
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Original Articles

Hepatic neoplasm

Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial: Sun Young Yim, Sung Hwan Lee, Seung-Woo Baek, Bohwa Sohn, Yun Seong Jeong, Sang-Hee Kang, Kena Park, Hyewon Park, Sunyoung S. Lee, Ahmed O. Kaseb, Young Nyun Park, Sun-Hee Leem, Michael A. Curran, Ji Hoon Kim, Ju-Seog Lee; Clin Mol Hepatol 2024;30(4):807-823.
Published online July 23, 2024; DOI: https://doi.org/10.3350/cmh.2024.0333

Background/Aims
Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge.
Methods
Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab.
Results
The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of antitumor macrophages and activated T-cells, potentially explaining its better response.
Conclusions
Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.

Citations

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Development and validation of a risk prediction model for patients with hepatocellular carcinoma receiving atezolizumab–bevacizumab
Heechul Nam, Dong Yun Kim, Do Young Kim, Ji Hoon Kim, Chang Wook Kim, Jaejun Lee, Keungmo Yang, Ji Won Han, Pil Soo Sung, Seung Kew Yoon, Hee Sun Cho, Hyun Yang, Si Hyun Bae, Soon Kyu Lee, Jung Hyun Kwon, Soon Woo Nam, Ahlim Lee, Do Seon Song, U Im Chang,
Hepatology.2026; 83(5): 1098. CrossRef
Baseline and dynamic cytokines as biomarkers for immune checkpoint and anti-VEGF therapy in advanced hepatocellular carcinoma
H.C. Wilbur, L.X. Zhao, M. Nakazawa, C. Kao, J.D. Gordan, T.P. Gade, L. Cope, L.T. Kagohara, D. Zabransky, W.J. Ho, M. Baretti, M. Yarchoan
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Significance of Measuring Interferon-γ-Induced Protein-10 Levels in Patients Receiving Systemic Therapies for Unresectable Hepatocellular Carcinoma
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Kuan-Chang Lai, San-Chi Chen
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Soon Kyu Lee, Bo Hyun Kim
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Mohammad Saeid Rezaee-Zavareh, Soo Young Hwang, Naomy Kim, Hasmik Adetyan, Nguyen H. Tran, Ju Dong Yang
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Hyewon Park, Sowon Park, Kena Park, Sun Young Yim, Ju-Seog Lee, Sung Hwan Lee
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Ruixin Chun, Haisen Ni, Ziyi Zhao, Chunlong Zhang
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Lixin Zhang, Yan Guo
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Hepatic neoplasm

Genetically-modified, redirected T cells target hepatitis B surface antigen-positive hepatocytes and hepatocellular carcinoma lesions in a clinical setting: Xueshuai Wan, Karin Wisskirchen, Tao Jin, Lu Yang, Xiaorui Wang, Xiang’an Wu, Fang Liu, Yu Wu, Christy Ma, Yong Pang, Qi Li, Ke Zhang, Ulrike Protzer, Shunda Du; Clin Mol Hepatol 2024;30(4):735-755.
Published online May 29, 2024; DOI: https://doi.org/10.3350/cmh.2024.0058

Background/Aims
Hepatitis B virus (HBV)-DNA integration in HBV-related hepatocellular carcinoma (HBV-HCC) can be targeted by HBV-specific T cells. SCG101 is an autologous, HBV-specific T-cell product expressing a T-cell receptor (TCR) after lentiviral transduction recognizing the envelope-derived peptide (S_20-28) on HLA-A2. We here validated its safety and efficacy preclinically and applied it to an HBV-related HCC patient (NCT05339321).
Methods
Good Manufacturing Practice-grade manufactured cells were assessed for off-target reactivity and functionality against hepatoma cells. Subsequently, a patient with advanced HBV-HCC (Child-Pugh class A, Barcelona Clinic Liver Cancer stage B, Eastern Cooperative Oncology Group performance status 0, hepatitis B e antigen-, serum hepatitis B surface antigen [HBsAg]+, HBsAg+ hepatocytes 10%) received 7.9×10⁷ cells/kg after lymphodepletion. Safety, T-cell persistence, and antiviral and antitumor efficacy were evaluated.
Results
SCG101, produced at high numbers in a closed-bag system, showed HBV-specific functionality against HBV-HCC cells in vitro and in vivo. Clinically, treatment was well tolerated, and all adverse events, including transient hepatic damage, were reversible. On day 3, ALT levels increased to 1,404 U/L, and concurrently, serum HBsAg started decreasing by 3.84 log¹⁰ and remained <1 IU/mL for over six months. HBsAg-expressing hepatocytes in liver biopsies were undetectable after 73 days. The patient achieved a partial response according to modified RECIST with a >70% reduction in target lesion size. Transferred T cells expanded, developed a stem cell-like memory phenotype, and were still detectable after six months in the patient’s blood.
Conclusions
SCG101 T-cell therapy showed encouraging efficacy and safety in preclinical models and in a patient with primary HBV-HCC and concomitant chronic hepatitis B with the capability to eliminate HBsAg⁺ cells and achieve sustained tumor control after single dosing.

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Letter to the Editor

Steatotic liver disease

Changing from NAFLD to MASLD: Similar prognosis of patients with HCC under atezolizumab/bevacizumab treatment between NAFLD and MASLD

Hiroyuki Suzuki, Shigeo Shimose, Hideki Iwamoto, Takashi Niizeki, Takumi Kawaguchi

Clin Mol Hepatol 2024;30(2):263-265.
Published online January 18, 2024

DOI: https://doi.org/10.3350/cmh.2023.0557

PDF

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Pathogenic Mechanisms of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)-Associated Hepatocellular Carcinoma
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Review

Hepatic neoplasm

Recent advances in the management of hepatocellular carcinoma

Kamya Sankar, Jun Gong, Arsen Osipov, Steven A. Miles, Kambiz Kosari, Nicholas N. Nissen, Andrew E. Hendifar, Ekaterina K. Koltsova, Ju Dong Yang

Clin Mol Hepatol 2024;30(1):1-15.
Published online July 21, 2023

DOI: https://doi.org/10.3350/cmh.2023.0125

Abstract

PDF

Liver cancer remains a challenge of global health, being the 4th leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and is usually precipitated by chronic viral infections (hepatitis B and C), non-alcoholic steatohepatitis, heavy alcohol use, and other factors which may lead to chronic inflammation and cirrhosis of the liver. There have been significant advances in the systemic treatment options for HCC over the past decades, with several approvals of both immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with preserved liver function. These advances have led to improvement in survival outcomes, with expected survival of greater than 18 months, in those with sensitive tumors, adequate liver function, and those functionally fit to receive sequential therapies. Several ongoing and promising trials are now evaluating combinational strategies with novel systemic agents and combinations of systemic therapy with locoregional therapy. In view of these trials, further advances in the treatment of HCC are foreseen in the near future.

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A Self-assembly Carrier-Free Nanovaccine based on Fluorinated CpG and Neoantigen Peptides for Hepatocellular Carcinoma Immunotherapy
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Ansofaxine Hydrochloride inhibits hepatocellular carcinoma growth and enhances targeted therapy through the EGFR/MAPK pathway
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MED10 as a Novel Oncogenic Driver in HCC: Promoting Cell Cycle Progression and Proliferation Through RAF1 Activation
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STOML2 inhibits sorafenib-induced ferroptosis in hepatocellular carcinoma via p-AKT signaling pathway
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Combined Analysis of Protein Induced by Prothrombin Induced by Vitamin K Absence (PIVKA) and Alpha-L-Fucosidase (AFU) with Alpha-Fetoprotein (AFP) May Improve the Diagnostic Efficacy for Liver Cirrhosis and Hepatocellular Carcinoma in Chronic Hepatitis B
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International Journal of General Medicine.2025; Volume 18: 6031.     CrossRef
Binding and ubiquitination-mediated degradation of ACKR3 by the novel Scutellarein derivative TBS6b potently suppresses hepatocellular carcinoma
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CDC5L binds to ELAVL1 to inhibit pyroptosis in hepatocellular carcinoma through the Caspase 3/GSDME signaling pathway
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Establishing a nomogram for post-hepatectomy liver failure prediction in hepatocellular carcinoma based on pre-operative and perioperative parameters
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Editorial

Hepatic neoplasm

Management of hepatocellular carcinoma in China: Seeking common grounds while reserving differences

Tian Yang, Ming-Da Wang, Xin-Fei Xu, Chao Li, Han Wu, Feng Shen

Clin Mol Hepatol 2023;29(2):342-344.
Published online March 16, 2023

DOI: https://doi.org/10.3350/cmh.2023.0106

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Snapshot

Hepatic neoplasm

Systemic therapy in advanced hepatocellular carcinoma

Joseph C. Ahn, Nguyen H. Tran, Ju Dong Yang

Clin Mol Hepatol 2023;29(2):516-519.
Published online February 20, 2023

DOI: https://doi.org/10.3350/cmh.2023.0051

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Comparative effectiveness of immunotherapy versus lenvatinib in advanced hepatocellular carcinoma: A real-world analysis using target trial emulation
Joseph C. Ahn, Wee Han Ng, Yee Hui Yeo, Hyun-Seok Kim, Yun Wang, Hirsh Trivedi, Walid S. Ayoub, Alexander Kuo, Nicole Rich, Neehar D. Parikh, Ghassan K. Abou-Alfa, Kevin Sheng-Kai Ma, Amit G. Singal, Ju Dong Yang
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Hee Sun Cho, Soon Kyu Lee
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Disparities in Immunotherapy Use Prior to First-Line Approval for Metastatic Hepatocellular Carcinoma in the United States
Manav Shah, Abdullah Khalid, Oliver Standring, Neda Amini, Lyudmyla Demyan, Shruti Koti, Emma Gazzara, Grace Wu, Nandan Vithlani, Danielle DePeralta, Sepideh Gholami, Matthew Weiss
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Current Landscape of Adoptive Cell Therapy and Challenge to Develop “Off‐The‐Shelf” Therapy for Hepatocellular Carcinoma
Seung Kak Shin, Yuta Mishima, Yoonseok Lee, Oh Sang Kwon, Ju Hyun Kim, Yun Soo Kim, Shin Kaneko
Journal of Gastroenterology and Hepatology.2025; 40(4): 791.     CrossRef
Landscape of T-cell exhaustion heterogeneity and HBV integration in virus-related HCC revealed by whole-exome, transcriptome, and single-cell sequencing
Soon Kyu Lee, Jinyeong Lim, Joo Yeon Jhun, Jeonghyeon Moon, Hye Seon Kim, Jong Young Choi, Ho Joong Choi, Young Kyoung You, Ji Won Han, Pil Soo Sung, Kwon Yong Tak, Seung Kew Yoon, Woong-Yang Park, Mi-La Cho, Jeong Won Jang
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Frontiers in Immunology.2024;[Epub]     CrossRef
CCL5/CCR5/CYP1A1 pathway prompts liver cancer cells to survive in the combination of targeted and immunological therapies
Yafei Wang, Biao Gao, Tianyu Jiao, Wenwen Zhang, Huizhong Shi, Hao Jiang, Xuerui Li, Junfeng Li, Xinlan Ge, Ke Pan, Chonghui Li, Guankun Mao, Shichun Lu
Cancer Science.2024; 115(11): 3552.     CrossRef
An Early Increase in IL-10 and TNF-α Levels Following Atezolizumab Plus Bevacizumab Treatment Predicts Survival in Advanced Hepatocellular Carcinoma Patients: A Prospective Cohort Study
Soon Kyu Lee, Soon Woo Nam, Ji Won Han, Jung Hyun Kwon
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Overview of Asian clinical practice guidelines for the management of hepatocellular carcinoma: An Asian perspective comparison
Yuri Cho, Bo Hyun Kim, Joong-Won Park
Clinical and Molecular Hepatology.2023; 29(2): 252.     CrossRef
The prime time for management of hepatocellular carcinoma in Hong Kong
Landon L. Chan, Stephen L. Chan
Clinical and Molecular Hepatology.2023; 29(2): 345.     CrossRef
What should be done to reduce the discrepancy between guidelines and real-life practice for hepatocellular carcinoma in Korea?
Min Kyung Park, Yoon Jun Kim
Clinical and Molecular Hepatology.2023; 29(2): 332.     CrossRef

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Reviews

Hepatic neoplasm

Clinical practice guidelines and real-life practice on hepatocellular carcinoma: A the Hong Kong perspective

Rex Wan-Hin Hui, Lung-Yi Mak, Tan-To Cheung, Victor Ho-Fun Lee, Wai-Kay Seto, Man-Fung Yuen

Clin Mol Hepatol 2023;29(2):217-229.
Published online December 28, 2022

DOI: https://doi.org/10.3350/cmh.2022.0399

Abstract

PDF

Hepatocellular carcinoma (HCC) is a major public health burden in Hong Kong, and chronic hepatitis B is the most common HCC etiology in our region. With the high case load, extensive local expertise on HCC has been accumulated. This article summarized local guidelines and real-life practice on HCC management in Hong Kong. For HCC surveillance, liver ultrasound and serum alpha-fetoprotein for periodic screening is recommended in viral hepatitis or cirrhotic patients, and this is adhered to in clinical practice. HCC diagnosis is not covered in local guidelines, yet our practice is in-line with regional guidelines, where diagnosis is usually achieved by cross-sectional imaging and without the need for histology. Our guidelines recommend using the Hong Kong Liver Cancer Staging for pre-treatment staging, yet we routinely use other widely-adopted systems such as the Barcelona Clinic Liver Cancer Staging and the Tumor-Node-Metastasis Staging as well. Our local guidelines have provided clear treatment algorithms for the whole range of HCC therapies, including resection, ablation, transplant, transarterial chemoembolization, transarterial radioembolization, stereotactic body radiation therapy, targeted therapy, and immunotherapy. Real-life treatment choices are largely in line with the guidelines, although treatment protocols are individualized, and availability of specific therapies can vary between centers. Overall, HCC guidelines in Hong Kong are tailored based on local expertise and our unique patient population. The guidelines are up-to-date and provide practical pathways to assist our routine practice. Regular updates of local guidelines are warranted to account for the rapidly evolving paradigm of HCC management.

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Hepatocellular carcinoma: Advances in systemic therapies
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Crosstalk between tumor-associated macrophages and neighboring cells in hepatocellular carcinoma

Pil Soo Sung

Clin Mol Hepatol 2022;28(3):333-350.
Published online October 19, 2021

DOI: https://doi.org/10.3350/cmh.2021.0308

Abstract

PDF

The tumor microenvironment generally shows a substantial immunosuppressive activity in hepatocellular carcinoma (HCC), accounting for the suboptimal efficacy of immune-based treatments for this difficult-to-treat cancer. The crosstalk between tumor cells and various cell types in the tumor microenvironment is strongly related to HCC progression and treatment resistance. Monocytes are recruited to the HCC tumor microenvironment by various factors and become tumor-associated macrophages (TAMs) with distinct phenotypes. TAMs often contribute to weakened tumor-specific immune responses and a more aggressive phenotype of malignancy. Recent single-cell RNA-sequencing data have demonstrated the central roles of specific TAMs in tumorigenesis and treatment resistance by their interactions with various cell populations in the HCC tumor microenvironment. This review focuses on the roles of TAMs and the crosstalk between TAMs and neighboring cell types in the HCC tumor microenvironment.

Citations

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Original Article

Hepatic neoplasm

Radiation-induced abscopal effect and its enhancement by programmed cell death 1 blockade in the hepatocellular carcinoma: A murine model study

Gyu Sang Yoo, Won-Gyun Ahn, Shin-Yeong Kim, Wonseok Kang, Changhoon Choi, Hee Chul Park

Clin Mol Hepatol 2021;27(1):144-156.
Published online December 7, 2020

DOI: https://doi.org/10.3350/cmh.2020.0095

Abstract

PDF
Supplementary Material

Background/Aims
The abscopal effect, a rare phenomenon induced by radiation, can be reinforced by immunotherapy. Although radiation therapy and immunotherapy are increasingly being utilized for the treatment of hepatocellular carcinoma (HCC), whether immunotherapy could boost the abscopal effect remains unclear. In this study, we aimed to elucidate the immunological mechanisms underlying the abscopal effect induced by the combination of irradiation and immunotherapy in a murine HCC model.
Methods
A syngeneic HCC mouse model was established by transplanting murine Hepa 1–6 HCC cells into both hind legs of immunocompetent C57BL/6 mice. The tumors on the right hind legs were irradiated, and abscopal effects were observed in the non-irradiated tumors on the left hind leg with or without the coadministration of anti-programmed cell death 1 (PD-1) antibodies. Flow cytometric analyses were performed to analyze the distributions of immune cells infiltrating both irradiated and non-irradiated tumors and the tumor-draining lymph nodes (TDLNs).
Results
Administration of 16 Gy in two fractions more effectively inhibited the growth of both irradiated and nonirradiated tumors with higher tumor infiltration of cytotoxic T cells than 8 Gy did in a single fraction. The higher dose also increased activated dendritic cells in TDLNs, which had higher expression of the programmed cell death ligand 1. Coadministration of anti-PD-1 antibodies significantly enhanced the abscopal effect and increased infiltration of activated cytotoxic T cells in both irradiated and non-irradiated tumors.
Conclusions
Our findings show that adding anti-PD-1 therapy to radiation enhanced the abscopal effect in a syngeneic murine model of HCC.

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Editorial

Hepatic neoplasm

Long-term prognosis and management of hepatocellular carcinoma after curative treatment

Naoshi Nishida

Clin Mol Hepatol 2020;26(4):480-483.
Published online September 21, 2020

DOI: https://doi.org/10.3350/cmh.2020.0208

PDF

Citations

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Isabella R. Buonopane, Erick F. Saldanha, Júnior Samuel Alonso de Menezes, Lucas Diniz da Conceição, Camila Mariana de Paiva Reis, Luís Felipe Leite, Thiago Francischetto, Renata D’Alpino Peixoto, Tiago Biachi de Castria
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Chengzi Sun, Jiahui Zhou
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European Journal of Medical Research.2025;[Epub]     CrossRef
Statistical Cure After Hepatectomy for Hepatitis B Virus-Associated Hepatocellular Carcinoma: A Risk-Stratification Model
Yi-Fan Li, Lan-Qing Yao, Chao Li, Hong Ren, Jin-Bo Gong, Han Wu, Li-Hui Gu, Ying-Jian Liang, Yu-Ze Yang, Kong-Ying Lin, Zi-Qiang Li, Qi-Xuan Zheng, Ting-Hao Chen, Ya-Hao Zhou, Hong Wang, Hong-Wei Guo, Jia-Hao Xu, Zhong Chen, Feng Shen, Ming-Da Wang, Tian
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Magnetic resonance elastography as a preoperative assessment for predicting intrahepatic recurrence in patients with hepatocellular carcinoma
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Magnetic Resonance Imaging.2024; 109: 127.     CrossRef
Sorafenib versus nivolumab after lenvatinib treatment failure in patients with advanced hepatocellular carcinoma
Yuna Kim, Jae Seung Lee, Hye Won Lee, Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Myung Ji Goh, Wonseok Kang, Seung Up Kim
European Journal of Gastroenterology & Hepatology.2023; 35(2): 191.     CrossRef
Development and validation of a nomogram for survival prediction in hepatocellular carcinoma after partial hepatectomy
Yang Lu, Shuang Ren, Jianning Jiang
BMC Surgery.2023;[Epub]     CrossRef
Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma in the era of chemo-diversity
Hideki Iwamoto, Shigeo Shimose, Tomotake Shirono, Takashi Niizeki, Takumi Kawaguchi
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Diagnosis of primary clear cell carcinoma of the liver based on Faster region-based convolutional neural network
Bin Liu, Jianfei Li, Xue Yang, Feng Chen, Yanyan Zhang, Hongjun Li
Chinese Medical Journal.2023; 136(22): 2706.     CrossRef
Ketogenic Diets and Hepatocellular Carcinoma
Yan Lan, Chaonan Jin, Pavitra Kumar, Xia Yu, Cameron Lenahan, Jifang Sheng
Frontiers in Oncology.2022;[Epub]     CrossRef
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Jie Zhang, Shang Dong Qin, Yan Li, Fei Lu, Wen Feng Gong, Jian Hong Zhong, Liang Ma, Jing Fei Zhao, Guo Hua Zhan, Peng Zhan Li, Bin Song, Bang De Xiang
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Real-Life Experience of mTOR Inhibitors in Liver Transplant Recipients in a Region Where Living Donation Is Predominant
Pil Soo Sung, Ji Won Han, Changho Seo, Joseph Ahn, Soon Kyu Lee, Hee Chul Nam, Ho Joong Choi, Young Kyoung You, Jeong Won Jang, Jong Young Choi, Seung Kew Yoon
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Metformin and Dichloroacetate Suppress Proliferation of Liver Cancer Cells by Inhibiting mTOR Complex 1
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Chao-Wei Lee, Sey-En Lin, Ming-Chin Yu, Hao-Wei Kou, Cheng-Han Lee, Tony Kuo, Kuan-Chieh Lee, Hsin-I Tsai
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Immunological Markers, Prognostic Factors and Challenges Following Curative Treatments for Hepatocellular Carcinoma
Soon Kyu Lee, Sung Won Lee, Jeong Won Jang, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon
International Journal of Molecular Sciences.2021; 22(19): 10271.     CrossRef

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Review

Hepatic neoplasm

Treatment options after sorafenib failure in patients with hepatocellular carcinoma

Imane El Dika, Ghassan K. Abou-Alfa

Clin Mol Hepatol 2017;23(4):273-279.
Published online November 20, 2017

DOI: https://doi.org/10.3350/cmh.2017.0108

Abstract

PDF

Second line therapy after failure of sorafenib continues to be under study. Prognosis of hepatocellular carcinoma is measured in months, with median overall survival reaching 10.7 months with sorafenib. Because of the modest net benefit sorafenib has contributed, and rising incidence of hepatocellular carcinoma in the world, continued efforts are ongoing to look for efficient upfront, second line, or combination therapies. Herein we review the most relevant to date published literature on treatment options beyond sorafenib, reported studies, ongoing investigational efforts, and possibilities for future studies in advanced hepatocellular carcinoma.

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