Oncolytic virotherapy at the tumor microenvironment-CAR Therapy interface: Mechanisms, clinical translation, and future directions.

Oncolytic virotherapy has evolved from a tumor-selective cytolytic strategy into a programmable immunotherapeutic platform that reshapes the tumor microenvironment (TME). Oncolytic viruses (OVs) selectively infect malignant cells, induce immunogenic cell death, release tumor antigens, and activate innate and adaptive immunity, potentially converting cold tumors into inflamed states. However, clinical translation remains limited by antiviral clearance, heterogeneous delivery, stromal barriers, immunosuppressive cells, and incomplete integration with cellular immunotherapy. This review synthesizes these mechanisms, platforms, and translational challenges. This review emphasizes platform-specific interactions between oncolytic viruses (OVs) and CAR-T, CAR-NK, and tumor-infiltrating lymphocyte (TIL) therapies. OVs may enhance CAR-T trafficking, antigen availability, local immune activation, and resistance to suppressive tumor microenvironmental signals. In CAR-NK therapy, OV-mediated cytokine support and TME remodeling may improve recruitment and activity, although antiviral NK responses can limit viral persistence. TIL therapy is considered separately because it relies on endogenous tumor-antigen recognition rather than engineered CAR targeting. Overall, direct OV-CAR evidence remains largely preclinical and platform-specific, while early clinical experience is more established for OV combinations with TILs and other immunotherapies in human studies. However, these mechanisms are supported predominantly by preclinical and early translational evidence, and direct clinical validation of OV-CAR combinations remains limited. Antiviral clearance, heterogeneous intratumoral infection, neutralizing immunity, delivery constraints, and potentially overlapping inflammatory toxicities may also restrict therapeutic synergy. Finally, we propose biomarker-driven trial designs that incorporate viral pharmacology, TME conversion, antigen-presentation competence, cellular-product persistence, and response assessment in injected and non-injected lesions.