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

Authors

Ding Hu, Qiong Wang

Published in

Frontiers in cell and developmental biology. Volume 14. Pages 1959317. Epub Oct 07, 2026.

Abstract

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.

PMID:
42909267
Bibliographic data and abstract were imported from PubMed on 23 Oct 2026.

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