Genetic engineering of systemically injectable oncolytic viruses for pyroptosis-accelerated cancer virotherapy
Menée à l'aide de lignées cellulaires, de xénogreffes sur des modèles murins, d'échantillons sanguins et d'échantillons tumoraux d'origine humaine, cette étude met en évidence l'intérêt thérapeutique de membranes cellulaires génétiquement modifiées et immunocompatibles exprimant un récepteur antigénique chimérique permettant de dissimuler des adénovirus oncolytiques qui codent pour une gasdermine N-terminal capable, sous ultrasons, de déclencher la mort des cellules cancéreuses par pyroptose
Systemic delivery of oncolytic viruses (OVs) is limited by neutralizing antibodies and poor intratumoral bioavailability. Here we developed genetically engineered, immune-compatible cell membranes expressing a chimeric antigen receptor to cloak OVs, creating a tumor-targeted viral delivery platform (iNV-GOV) that shields virions from immune recognition while guiding them to tumors. The OV payload encodes an N-terminal gasdermin under a heat-shock promoter enabling ultrasound-induced mild hyperthermia to trigger tumor-specific pyroptosis, accelerate oncolysis and promote rapid viral release from lysed tumor cells, thereby amplifying infection of neighboring tumor populations. Following systemic administration, iNV-GOV efficiently targets and infects tumor cells, induces pyroptosis upon ultrasound activation and elicits robust antitumor immunity in patient-derived xenograft models in humanized mice. Collectively, this systemically injectable, tumor-targeted OV platform enables rapid and continuous intratumoral viral propagation and represents a promising strategy for treating a wide range of cancers.
Nature Cancer , article en libre accès, 2026