A modified oncolytic measles virus exhibits strong immunotherapeutic potential through RIG-I activation by defective viral genomes
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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.
IMPACT Statement
This study presents a rationally engineered measles vaccine virus (MVdeltaC) lacking the nonstructural regulatory C protein that plays a central role in antagonizing the host innate immune response. This virus redirects viral replication toward immune activation through defective viral RNA generation triggering RIG-I–mediated innate sensing. MVdeltaC induces immunogenic tumor cell death, enhances antigen-presenting cell activation, and drives potent CD8+ T and NK cell–dependent antitumor responses in vivo resulting in potent tumor rejection. Its efficacy is further amplified by checkpoint blockade or preexisting measles immunity, supporting its clinical potential as a next-generation broad-spectrum immuno-oncolytic therapy that synergizes with and builds upon existing immunotherapies.
