Advanced hepatocellular carcinoma in the immunotherapy era: real-world immune dynamics and multidisciplinary strategies beyond clinical trials

The immunotherapy revolution has fundamentally altered the treatment landscape of advanced hepatocellular carcinoma (HCC), yet the immune biology underlying real-world clinical responses remains incompletely understood. Randomized trials, while foundational, enroll carefully selected populations that rarely reflect the immune complexity encountered in everyday practice — patients with HBV- or HCV-driven immune dysregulation, MASLD/MASH- or alcohol-related metabolic inflammation, cirrhosis-related immunosuppression, portal hypertension, or prior locoregional treatment-induced immune remodeling. These factors profoundly shape the tumor immune microenvironment (TIME), influence responses to immune checkpoint inhibitors (ICIs), and drive patterns of resistance and toxicity that trials are not designed to capture.Across Asia-Pacific institutions, where HBV-associated HCC remains highly prevalent, while non-viral HCC associated with lifestyle-related liver diseases — including MASLD/MASH- and alcohol-related liver disease — is rapidly increasing, a distinct body of immunological knowledge has emerged. In parallel, metabolic liver disease may generate a chronically inflamed yet immunologically dysfunctional hepatic milieu, potentially altering ICI responsiveness, resistance patterns, and liver-specific toxicity. Locoregional therapies — including TACE, HAIC, and ablation — induce immunogenic cell death, promote tumor antigen release, and remodel intratumoral immune contextures in ways that may prime or antagonize subsequent ICI therapy. Treatment sequencing decisions are therefore not merely logistical but carry direct immunological consequences that remain undercharacterized in real-world, heterogeneous populations. Similarly, the management of immune-related adverse events (irAEs) in patients with underlying liver disease presents unique immunological challenges rarely addressed in trial-based literature.This Research Topic aims to bridge immunological science and real-world clinical evidence in advanced HCC, with particular emphasis on the Asia-Pacific context, where viral, metabolic, and alcohol-related etiologies coexist and shape distinct immune landscapes. It focuses on how treatment-induced immune dynamics — captured through multicenter studies, institutional cohorts, and registry-based analyses — can inform patient selection, sequencing strategies, and irAE management beyond the scope of conventional trials.We welcome original research, translational studies, multicenter analyses, and expert reviews addressing, but not limited to, the following themes:o Immune contexture of HBV- and HCV-associated HCC and its impact on ICI response in real-world populationso Immunomodulatory effects of locoregional therapies (TACE, HAIC, ablation, SBRT) on the TIME and subsequent ICI efficacyo Immune biomarkers for patient selection and treatment monitoring in non-trial settingso Immune consequences of treatment sequencing in the ICI erao Immunological mechanisms and management of irAEs in patients with underlying liver disease and cirrhosiso Liver-specific immune tolerance and its role in shaping ICI resistance in real-world cohortso HBV reactivation and immune modulation during combination immunotherapyo Multicenter, registry-based, and propensity score–matched studies addressing immune outcomes in advanced HCCo Metabolic and steatohepatitis-driven immune remodeling in established advanced HCC and its real-world impact on ICI response, resistance, and toxicityBy connecting immunological mechanisms to real-world therapeutic decisions — and by centering the Asia-Pacific experience where the immune landscape of HCC is distinctly shaped by viral, metabolic, and alcohol-related etiologies as well as established locoregional practice — this Research Topic offers a perspective that neither mechanistic nor trial-based literature has fully captured.Please note that Dr. Sadahisa Ogasawara works with the following companies: Eisai, Chugai Pharma, AstraZeneca, Takeda, AbbVie, Gilead Sciences, Merck & Co., Inc., Bristol Myers Squibb, Ono, and Daiichi Sankyo (honoraria, consulting/advisory roles, and/or research grants).Please note that Prof. Hong Jae Chon works with the following companies: Eisai, Roche, Ono Pharmaceutical, MSD, Bristol Myers Squibb, BeOne Medicines, Servier, AstraZeneca, Sanofi, Aptamer Science, Boryung, Medivir, Guardant Health, IMBDx, Dong-A ST (honoraria, consulting/advisory roles, and/or research grants).Please note that Dr. Takanori Ito works with the following companies: AbbVie, AstraZeneca, Bristol Myers Squibb, Canon Medical Systems Corporation, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Gilead Sciences, Kowa Company, MSD, Nobelpharma, Ono Pharmaceutical, Taisho Pharmaceutical, Takeda, and Zeria Pharmaceutical (honoraria, consulting/advisory roles, and/or research grants).Please note that Dr. Hidekatsu Kuroda works with the following companies: Eisai, Chugai Pharma, AstraZeneca, Takeda, and Bristol Myers Squibb (honoraria). Topic editors: Takanori Ito, Sadahisa Ogasawara, HONG JAE CHON, Hiroaki Kanzaki, Hidekatsu Kuroda Source: https://www.frontiersin.org/research-topics/83129/advanced-hepatocellular-carcinoma-in-the-immunotherapy-era-real-world-immune-dynamics-and-multidisciplinary-strategies-beyond-clinical-trials