biostudies-literatureRajwani JCanadian Cancer Society Research Institute (Société Canadienne du Cancer)Alberta Children's Hospital FoundationNHLBI NIH HHSGouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)9933https://www.ebi.ac.uk/biostudies/studies/S-EPMC11567966biostudies-literatureUnknown15(1)Oncolytic viruses (OV) are designed to selectively infect and kill cancer cells, while simultaneously eliciting antitumour immunity. The mechanism is expected to originate from infected cancer cells. However, recent reports of tumour regression unaccompanied by cancer cell infection suggest a more complex mechanism of action. Here, we engineered vesicular stomatitis virus (VSV)^ΔM51-sensitive and VSV^ΔM51-resistant tumour lines to elucidate the role of OV-infected cancer and non-cancer cells. We found that, while cancer cell infections elicit oncolysis and antitumour immunity as expected, infection of non-cancer cells alone can also contribute to tumour regression. This effect is partly attributed to the systemic production of cytokines that promote dendritic cell (DC) Nature communicationsVSV<sup>∆M51</sup> drives CD8<sup>+</sup> T cell-mediated tumour regression through infection of both cancer and non-cancer cells.PMC11567966156035ACHF21-084575N92020D00005ACTION-20420828Vishnevskiy DMah LKMonument MJGonzales GARajwani JChan JAChanda AZemp FJHyrcza MGafuik CTodesco HMMahoney DJPotts KGLau KCKKim DSNaumenko VTurk MHildebrand KMCanton JLiao SXue JJenne CNSnelling SBose PfalseVSV<sup>∆M51</sup> drives CD8<sup>+</sup> T cell-mediated tumour regression through infection of both cancer and non-cancer cells.Oncolytic viruses (OV) are designed to selectively infect and kill cancer cells, while simultaneously eliciting antitumour immunity. The mechanism is expected to originate from infected cancer cells. However, recent reports of tumour regression unaccompanied by cancer cell infection suggest a more complex mechanism of action. Here, we engineered vesicular stomatitis virus (VSV)^ΔM51-sensitive and VSV^ΔM51-resistant tumour lines to elucidate the role of OV-infected cancer and non-cancer cells. We found that, while cancer cell infections elicit oncolysis and antitumour immunity as expected, infection of non-cancer cells alone can also contribute to tumour regression. This effect is partly attributed to the systemic production of cytokines that promote dendritic cell (DC) 2024-01-01T00:00:00Z2024 Nov2026-06-03T03:13:04.967Z2025-04-06T22:42:57.061ZS-EPMC115679663954807010.1038/s41467-024-54111-6