Oncolytic virus-delivered GSDME: Unlocking pyroptosis to improve dendritic cell function and amplify cytotoxic T cell...

Oncolytic virotherapy is a promising strategy for advanced cancers, but clinical success remains limited. Combining oncolytic viruses with immunogenic cell death modalities offers a potential solution. Pyroptosis, an inflammatory form of programmed cell death mediated by gasdermin proteins, amplifies anti-tumor immune responses through the release of damage-associated molecular patterns. Gasdermin E can switch apoptosis to pyroptosis upon caspase-3 cleavage, but its therapeutic potential is limited due to silenced expression in tumors. Here, we engineered the chimeric Vesicular stomatitis virus (VSV)-GP to express full-length GSDME, enabling pyroptosis induction in GSDME-deficient tumors. VSV-GP-GSDME efficiently delivered GSDME to tumor cells, leading to caspase-3-dependent pyroptotic cell death while retaining replication kinetics and achieving higher therapeutic potency. In vitro, VSV-GP-GSDME shifted cell death from apoptosis to pyroptosis, enhancing tumor cell immunogenicity. In vivo, it improved tumor control, prolonged survival, and promoted dendritic cell activation and tumor-infiltrating CD8 T cell expansion with cytotoxic phenotypes. Thus, VSV-GP-GSDME combines VSV-GP's oncolytic activity with GSDME-mediated pyroptosis to induce anti-tumor immunity. This dual mechanism broadens applicability across diverse tumors, offering a promising strategy to enhance immunogenicity.