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

Authors

Sabrina Schneider, Theresa Schwaiger, Joelle Kröll, Ioannes Basbas, Fabian Martin, Dongyue Xin, Elke Podgorschek, Ilona Arnkil, Marlies Glatz, Melissa Mayr, Monika Petersson, Stefan Scheidl, Stefan Schneeberger, Krishna Das, Bart Spiesschaert, Christian Mandl, Sebastian Carotta, Christiane B Knobbe-Thomsen, Knut Elbers, Tobias Nolden

Published in

Molecular therapy. Oncology. Volume 34. Issue 3. Pages 201264. Sep 17, 2026. Epub Jun 11, 2026.

Abstract

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.

PMID:
42405006
Bibliographic data and abstract were imported from PubMed on 06 Jul 2026.

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