A modified oncolytic measles virus exhibits strong immunotherapeutic potential through RIG-I activation by defective viral genomes

Live-attenuated measles virus (MV) infects cancer cells through the CD46 receptor, commonly overexpressed in tumors, and replicates preferentially in cells with impaired type I interferon (IFN-I) response. To enhance immune stimulation, we engineered a C protein–deficient MV (MVdeltaC), thus eliminating a key viral antagonist of innate immunity. MVdeltaC exhibited potent oncolytic activity in a broad panel of human tumor cell lines, with a vast majority of them showing high sensitivity. This enhanced efficacy is dependent on RIG-I stimulation, mainly through the generation of defective viral genomes, which trigger apoptosis, robust IFN-I signaling and massive CXCL10 production. MVdeltaC infection induced immunogenic cell death, the release of danger signals, and the maturation of dendritic cells. In vivo, MVdeltaC significantly reduced tumor burden in xenografts and patient-derived xenograft (PDX) models. Intratumoral MVdeltaC administration in immunocompetent A/J mice grafted with syngeneic neuroblastoma led to complete tumor rejection in 90% of animals and long-term antitumor memory. Efficacy was dependent on CD8+ T and NK cells and was further enhanced by anti- CTLA-4 treatment or CD4+ T cell depletion. Prior measles immunization accelerated tumor clearance, indicating memory-boosted antitumor responses. These findings support the clinical potential of MVdeltaC as a strong RIG-I activator for next-generation large-spectrum anticancer therapy.