Oncolytic Virus-Based Immunotherapy: Mechanistic Insights, Synergistic Design and Translational Frontiers

Oncolytic viruses (OVs) can selectively lyse tumor cells and remodel the immunosuppressive tumor microenvironment. However, monotherapy is limited by low response rates, systemic delivery barriers and antiviral-mediated viral clearance. Combinatorial strategies with immune-checkpoint inhibitors, CAR-T cells, cancer vaccines, microbiota intervention, chemotherapy and radiotherapy produce potent synergistic antitumor effects. Herein, we review the spatiotemporal-dependent synergistic mechanisms by which OVs convert “cold” tumors into immunologically “hot” lesions, alongside recent pre-clinical and clinical progress of various combination regimens. We further discuss major bottlenecks including unstable efficacy, cumulative toxicity and translational obstacles. Several promising biomarkers, such as baseline TME immunophenotypes, dynamic neutralizing-antibody kinetics, STING-IFN signaling and gut microbiota, support individualized OV-based therapy. Finally, we outline near-term sequential-optimization strategies and long-term directions centered on intelligently engineered OVs and multi-modal combinatorial platforms, offering guidance for future rational design of oncolytic viro-immunotherapy.