{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:32:59Z","timestamp":1787149979033,"version":"build-2736575974"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Atezolizumab-bevacizumab and durvalumab-tremelimumab have established immunotherapy as a first-line standard of care in advanced hepatocellular carcinoma (HCC). Yet, objective response rates (ORRs) remain confined to approximately 15-20%, and no validated predictive biomarker exists for patient selection. Unlike melanoma and lung cancer, conventional markers, including programmed death-ligand 1, microsatellite instability-high status, and tumor mutational burden, have not demonstrated reliable predictive value in HCC. Prior narrative reviews comprehensively catalogued the biomarker landscape through 2022 but predate a wave of clinically significant publications. This narrative review synthesizes evidence published between 2020 and 2026, with particular emphasis on 2023\u20132026 data, within a unified clinical framework not provided by prior reviews. We critically evaluate tissue-based biomarkers, including the AI-derived Atezolizumab-Bevacizumab Response Signature-Pathology model, spatial multiplex immunohistochemistry, and \u03b2-catenin mutational profiling; blood-based biomarkers encompassing circulating tumor DNA for minimal residual disease detection and peripheral immune phenotyping; and serum indices including the CRAFITY score and neutrophil-to-lymphocyte ratio. Hepatitis B virus etiology and non-alcoholic steatohepatitis are discussed as biological modifiers of biomarker performance. We propose an original biomarker-guided clinical algorithm, a comparative clinical readiness table, and a disease-continuum biomarker timeline as practical tools for clinicians and trialists. Prospective biomarker-enrichment trials represent the most critical next step toward clinical translation.<\/jats:p>","DOI":"10.3389\/fonc.2026.1894185","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:10:50Z","timestamp":1787148650000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tissue and blood-based predictive biomarkers in hepatocellular carcinoma immunotherapy: synthesis of 2023\u20132026 evidence and a proposed clinical integration framework"],"prefix":"10.3389","volume":"16","author":[{"given":"Ashish","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Yale New Haven Hospital","place":["New Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joecelyn Kirani","family":"Tan","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Medicine and Health, University of Manchester","place":["Manchester, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajvardhan","family":"Sisodia","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Mahatma Gandhi Memorial Medical College","place":["Indore, Madhya, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harendra","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hareesha Rishab","family":"Bharadwaj","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Royal Stoke University Hospital, University, Hospitals of North Midlands NHS","place":["Stoke-on-Trent, Staffordshire, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sneh","family":"Sonaiya","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Nevada","place":["Las Vegas, NV, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yash","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences","place":["Little Rock, AK, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassam","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Nutrition, East Carolina University\/Brody School of Medicine","place":["Greenville, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arkadeep","family":"Dhali","sequence":"additional","affiliation":[{"name":"Academic Unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahman Hameed 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