biostudies-literatureRios AVMayo Foundation for Medical Education and ResearchHyundai Hope On WheelsNIAID NIH HHSKing's College LondonUniversity of MinnesotaMayo ClinicNCI NIH HHSNational Institutes of HealthRichard M. Schulze Family Foundation5489-5504https://www.ebi.ac.uk/biostudies/studies/S-EPMC12502006biostudies-literatureUnknown33(11)Immune tolerance restricts the number of T cells with significant affinity for self-tumor-associated antigens (TAAs), thereby limiting successful cancer immunotherapy through an inability to generate populations of high-affinity anti-tumor T cells. In contrast, viral infection/vaccination primes and expands high-affinity effector and memory T cells against viral antigens. We show here that it is possible to exploit population-wide preexisting, anti-viral memory recall responses against SARS-CoV-2 antigens to focus a high-affinity, immunodominant T cell response into tumors by oncolytic virus (OV)-mediated or chimeric antigen receptor (CAR)-mediated delivery of viral antigens that are not themselves related to TAAs. Heterologous prime and OV/boost led to CD8⁺ T cell-dependent tumMolecular therapy : the journal of the American Society of Gene TherapyExploiting viral infection/vaccination to focus high-affinity T cell populations into tumors using oncolytic viro-immunotherapy.PMC12502006R01 AI170535P50 CA210964R01 CA269384CA210964-06A1 P3Tonne JMetko MVile RRios AVThompson JBarry MAKendall BMudrick HChen AIrshad SBarry MDiaz RMMasopust DfalseExploiting viral infection/vaccination to focus high-affinity T cell populations into tumors using oncolytic viro-immunotherapy.Immune tolerance restricts the number of T cells with significant affinity for self-tumor-associated antigens (TAAs), thereby limiting successful cancer immunotherapy through an inability to generate populations of high-affinity anti-tumor T cells. In contrast, viral infection/vaccination primes and expands high-affinity effector and memory T cells against viral antigens. We show here that it is possible to exploit population-wide preexisting, anti-viral memory recall responses against SARS-CoV-2 antigens to focus a high-affinity, immunodominant T cell response into tumors by oncolytic virus (OV)-mediated or chimeric antigen receptor (CAR)-mediated delivery of viral antigens that are not themselves related to TAAs. Heterologous prime and OV/boost led to CD8⁺ T cell-dependent tum2025-01-01T00:00:00Z2025 Nov2026-06-16T03:09:48.326Z2026-06-16T03:06:43.91ZS-EPMC125020064084215610.1016/j.ymthe.2025.08.023