Abstract 650: Enhancing antitumor immunity by inducing PANoptosis using a new generation of vesicular stomatitis virus

Abstract Despite significant advances, the limited therapeutic efficacy of virotherapy remains a major hurdle in the use of oncolytic viruses (OVs) for cancer treatment. To overcome this challenge, we integrated the SMAC/DIABLO gene into the genome of vesicular stomatitis virus (VSV) to create a new generation of VSV, termed VSV-S. In this study, we infected head and neck squamous cell carcinoma (HNSCC) cells and tumors with VSV-S to evaluate its therapeutic efficacy and underlying mechanisms. VSV-S exhibited significantly enhanced antitumor activity in HNSCC cells compared to the parental virus. It not only promoted cancer cell apoptosis through the overexpression of SMAC during VSV infection, but also induced PANoptosis (a combination of pyroptosis, apoptosis, and necroptosis) through the activation of caspase 3, gasdermin D and gasdermin E, and MLKL signaling pathways, which led to enhanced recruitment of CD8+ T cells to the tumor and eventually potentiated T cell-mediated antitumor immunity. In addition, VSV-S reduced PD-L1 levels in HNSCC cells and, when combined with anti-PD-1 antibody, produced a more potent antitumor effect than either treatment alone. These results provide valuable preclinical evidence to support the development of VSV-S-based antitumor therapies that could improve outcomes for patients with HNSCC. Citation Format: Fanghui Chen, Liwei Lang, Sijia Tang, Fan Yang, Nabil F. Saba, Ming Luo, Yong Teng. Enhancing antitumor immunity by inducing PANoptosis using a new generation of vesicular stomatitis virus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 650.