When oncolytic viruses get on CAR: a synergic approach for solid tumor immunotherapy

Abstract Chimeric antigen receptor (CAR)-based cell therapies have transformed the treatment of selected hematologic malignancies, yet their efficacy in solid tumors remains limited due to antigen heterogeneity, inadequate trafficking, physical and metabolic barriers, immune suppression, and poor persistence of transferred cells. Oncolytic viruses (OV) provide a complementary therapeutic platform because they can selectively infect and lyse tumor cells, release tumor antigens and danger signals, remodel the tumor microenvironment, and deliver immunomodulatory payloads directly into tumor tissue. Increasing evidence suggests that rational OV–CAR combinations can convert the tumor from a passive target into an active site of immune amplification. In this review, we discuss the biological rationale and emerging engineering strategies by which OVs can enhance CAR-T and CAR-NK cell therapy. We highlight mechanisms including immunogenic tumor debulking, OV-mediated delivery of synthetic or additional CAR target antigens, local expression of cytokines and chemokines, viral production of immune engagers and checkpoint modulators, and carrier-cell approaches that improve intratumoral delivery. We further use glioblastoma (GBM) as a case study to emphasize how viral antigen delivery and cytokine-armed OVs may address antigen escape, poor persistence, and the immunosuppressive brain tumor microenvironment. Finally, we outline translational challenges, including safety, antiviral immunity, dosing sequence, patient selection, and manufacturing. The next generation of OV–CAR therapy will likely require integrated design of the virus, immune effector cells, delivery route, and biomarker-guided clinical strategy.