Leveraging multimodal cancer immunotherapy to amplify the efficacy of oncolytic viruses.

Oncolytic viruses (OVs) represent a versatile platform for cancer immunotherapy, capable of selectively infecting and lysing tumor cells while triggering systemic antitumor immunity. However, their therapeutic efficacy remains limited by antiviral immunity, restricted intratumoral spread, and an immunosuppressive tumor microenvironment. This review highlights emerging strategies to potentiate OV efficacy through rational combination with complementary immunotherapies, including immune checkpoint inhibitors, adoptive cell therapies, cancer vaccines, and small-molecule immunomodulators. These synergistic interventions can remodel the tumor microenvironment, enhance immune cell infiltration and activation, reverse immunosuppressive feedback, promote immunogenic cell death, normalize the tumor vasculature, and modulate the gut microbiota, collectively amplifying OV replication and oncolytic potency. The integration of artificial intelligence and multiomics profiling further enables precise patient stratification and optimization of combination regimens. In parallel, advanced engineering strategies, such as arming OVs with immunomodulatory transgenes and mitigating host antiviral responses, further reinforce these effects. Together, these approaches illustrate how multimodal immunotherapy can overcome the intrinsic limitations of OVs, enabling durable antitumor immunity. This review underscores the central role of combination strategies in OV-based immuno-oncology and outlines future directions to accelerate their clinical translation.