{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:51:51Z","timestamp":1791359511586,"version":"4.3.1"},"reference-count":133,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"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. Cell Dev. Biol."],"abstract":"<jats:p>Hepatocellular carcinoma (HCC) develops in a chronically injured and immunologically specialized organ that is both the treatment target and a major determinant of viral clearance and toxicity. Oncolytic viruses (OVs) can couple tumor-selective infection with immunogenic lysis, innate sensing, antigen presentation, and adaptive immune recruitment, but the clinical consequences of these processes depend on viral platform, delivery route, liver-resident cell handling, spatial disease distribution, and hepatic reserve. This review synthesizes HCC OV biology across four linked levels: platform-specific tumor-cell susceptibility; replication and interferon restriction; regulation by Kupffer cells, liver sinusoidal endothelial cells, dendritic-cell subsets, hepatic stellate cells, fibroblasts, and resident lymphoid populations; and spatial pharmacodynamics across injected tumors, non-injected intrahepatic lesions, cirrhotic parenchyma, and extrahepatic disease. We compare adenovirus, vaccinia virus, herpes simplex virus, and candidate RNA viruses using route- and assay-matched criteria and interpret clinical evidence according to study design, biological context, and permissible inference. Early Pexa-Vec studies established biological activity, whereas PHOCUS defined a negative boundary for Pexa-Vec followed by sorafenib in an unselected first-line population. H101 plus nivolumab and VG161 support early feasibility and pharmacodynamic investigation, while integrated human pharmacodynamic and diseased-liver HCC-model reovirus data highlight schedule-dependent immune effects and potential off-tumor liver inflammation. VIRAL-HCC is used only as a non-scored organizational matrix for prospective trial design and biomarker interpretation. Future development should link tumor exposure and productive infection or payload expression to compartment-resolved immune effects, clinically relevant tumor control, and preservation of hepatic reserve.<\/jats:p>","DOI":"10.3389\/fcell.2026.1959317","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:12:31Z","timestamp":1791357151000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Liver-resident cellular determinants of oncolytic virotherapy in hepatocellular carcinoma: viral susceptibility and spatial immune remodeling"],"prefix":"10.3389","volume":"14","author":[{"given":"Ding","family":"Hu","sequence":"first","affiliation":[{"name":"Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"EVIDoa2100070","DOI":"10.1056\/evidoa2100070","article-title":"Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma","volume":"1","author":"Abou-Alfa","year":"2022","journal-title":"NEJM Evid."},{"key":"B2","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1159\/000533650","article-title":"PHOCUS: a phase 3, randomized, open-label study of sequential treatment with pexa-vec (JX-594) and sorafenib in patients with advanced hepatocellular carcinoma","volume":"13","author":"Abou-Alfa","year":"2024","journal-title":"Liver Cancer"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1099\/0022-1317-81-11-2605","article-title":"Blood clearance rates of adenovirus type 5 in mice","volume":"81","author":"Alemany","year":"","journal-title":"J. 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