Immune Checkpoint Inhibitors Combined with Oncolytic Virotherapy: Synergy, Heterogeneity, and Safety in Cancer Treatment.

Immune checkpoint inhibitor (ICI) has limited efficacy in the treatment of immune "cold" tumors. Due to insufficient T cell infiltration and heterogeneous programmed death ligand 1 (PD-L1) expression, the ORR is only 5%-8% compared with 30%-40% of "hot" tumors. This article reviews the synergistic mechanism, clinical efficacy and optimization strategy of oncolytic virus (OVs) combined with ICIs in the treatment of refractory malignant tumors. Systematic analysis of mechanistic interactions across tumor types and clinical trial data demonstrates that OVs transform the immunosuppressive microenvironment by inducing immunogenic cell death and activating innate immunity. Concurrently, ICIs enhance adaptive immunity by reversing T-cell exhaustion and expanding T-cell diversity. Clinical trials in melanoma, head and neck cancer and breast cancer showed superior efficacy. The Objective Response Rate (ORR) of combination therapy was 39%-62%, while the ORR of ICI monotherapy was 18%. Treatment heterogeneity is mainly attributed to virus-related factors, including targeting specificity and replication efficiency, tumor characteristics, such as antigen presenting ability and mutation load, and host immune status, including pre-existing antiviral antibodies and microbiome composition. This combined approach represents a paradigm shift in cancer immunotherapy, which effectively transforms immune "cold" tumors into "hot" tumors through the continuous activation of innate and adaptive immune responses. In the future, it is expected to improve the therapeutic effect of treatment-resistant malignant tumors through the integration of immune regulatory molecules, accurate biomarkers to guide the treatment scheme and triple combination strategy by a new generation of engineering viruses.