Liver-resident cellular determinants of oncolytic virotherapy in hepatocellular carcinoma: viral susceptibility and spatial immune remodeling.
- 1Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China.
- 2Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China.
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.
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BibTeX
@article{hu2026liverresident,
title = {{Liver-resident cellular determinants of oncolytic virotherapy in hepatocellular carcinoma: viral susceptibility and spatial immune remodeling.}},
author = {Ding Hu and Qiong Wang},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1959317},
url = {https://europepmc.org/article/MED/42909267},
note = {CC BY},
}
RIS
TY - JOUR
TI - Liver-resident cellular determinants of oncolytic virotherapy in hepatocellular carcinoma: viral susceptibility and spatial immune remodeling.
AU - Ding Hu
AU - Qiong Wang
PY - 2026
DA - 2026/10/07
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1959317
UR - https://europepmc.org/article/MED/42909267
AB - 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.
SN - 2296-634X
ER -