Viral-directed augmentation of Kupffer cell cross-presentation provokes anti-tumor 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 ability to capture circulating virions, we developed an oncolytic virus-based KC-targeting strategy that demonstrates 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 melanoma and colorectal cancer liver metastasis. The ineffectiveness of VSV-WT was ascribed to its rapid induction of KC apoptosis, whereas VSV-M51R transiently replicated within KCs without compromising their viability. Depleting KCs abolished the therapeutic effects of VSV-M51R. Mechanistically, VSV-M51R treatment promoted KCs proliferation in tumor-adjacent areas, enhancing their access to tumor foci, uptake of tumor-derived materials, and cross-presentation of tumor antigens, leading to a robust activation of hepatic anti-tumor CD8+T cell responses that required MAVS-dependent type I interferon triggering of KCs. Simultaneous blockade of PD-L1, which was upregulated on KCs during VSV-M51R treatment, achieved remarkable synergistic efficacy in late-stage liver metastasis. Our findings underscore the pivotal role of KCs in systemic oncolytic virotherapy and offers a potentially clinically applicable strategy for treating advanced liver metastasis.