Liver-resident cellular determinants of oncolytic virotherapy in hepatocellular carcinoma: viral susceptibility and spatial immune remodeling.

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.