VSV-CHIKV activates antitumor immunity by inducing pyroptosis in a melanoma model

Melanoma is the most dangerous skin cancer due to its difficulty in treatment, high recurrence rate and metastatic ability. As a vector for oncolytic viruses (OVs), vesicular stomatitis virus (VSV) has been shown to be effective against malignant melanoma. However, the glycoprotein G protein of VSV has potential neurotoxicity. It has been shown that replacing glycoprotein G with E3-E2-6K-E1 of chikungunya virus (CHIKV) reduces its neurotoxicity and targets gliomas. Therefore, the aim of this study was to investigate the oncolytic effect of recombinant VSV-CHIKV on melanoma and the underlying mechanism. In this study, we found that recombinant VSV-CHIKV triggered GSDMD-mediated melanoma cell pyroptosis. Importantly, the NLRP3/Caspase-1/GSDMD axis was activated after VSV-CHIKV infection in melanoma cell lines and in a xenograft mouse model. Inhibition of GSDMD blocked cell pyroptosis, antitumor immunity and the tumor response in response to VSV-CHIKV treatment, suggesting that VSV-CHIKV act through the GSDMD pathway. VSV-CHIKV-triggered GSDMD-mediated tumor pyroptosis recruited cytotoxic T lymphocytes (CTLs) into the tumor microenvironment, which was accompanied by the release of inflammatory mediators. This remodeled the tumor microenvironment and turned immunologically "cold" tumors into "hot" tumors, thereby sensitized these tumors to checkpoint blockade. Finally, the combination therapy of VSV-CHIKV and an immune checkpoint inhibitor (anti-PD-1) prolonged the survival of mice. In conclusion, the VSV-CHIKV strategy is an attractive biologic therapy against melanoma.