Viral-Directed Augmentation of Kupffer Cell Cross-Presentation Provokes Antitumor Immunity Against Liver Metastasis.

Liver metastasis is associated with poor prognosis and resistance to immune checkpoint inhibitors. Functional modulation of Kupffer cells (KCs) holds promise as an alternative immunotherapeutic approach. Leveraging their capacity to capture circulating virions, an oncolytic virus-based KC-targeting strategy is developed that demonstrated efficacy and safety in treating multifocal liver metastasis. A single intravenous infusion of the M51R mutant vesicular stomatitis virus (VSV-M51R), but not wild-type (WT) VSV, induced significant tumor regression in mouse models of forced liver metastasis, independent of direct oncolysis. The ineffectiveness of VSV-WT is attributed to its induction of massive KC apoptosis, whereas VSV-M51R replicated transiently within KCs without compromising viability. Instead, VSV-M51R promoted KC proliferation in tumor-adjacent areas, enhancing their access to tumor foci and cross-presentation of tumor antigens. This led to robust activation of hepatic anti-tumor CD8 T-cell responses, which required mitochondrial antiviral signaling protein-dependent type I interferon triggering in KCs. Depletion of KCs abolished the T cell stimulating and anti-tumor effects of VSV-M51R. Furthermore, simultaneous blockade of programmed cell death-ligand 1(PD-L1) during VSV-M51R treatment achieved remarkable synergistic efficacy in treating monotherapy-resistant late-stage liver metastasis. These findings underscore the pivotal role of KCs in systemic oncolytic virotherapy and offer a potentially applicable strategy for treating advanced liver metastasis.