Oncolytic immunovirotherapy: finding the tumor antigen needle in the antiviral haystack

Immunovirotherapy integrates the oncolytic capabilities of viruses with the modulation of the host immune system to establish robust tumor-specific immune responses. Oncolytic viruses (OVs) are natural or engineered viruses that specifically replicate in and lyse tumor cells, triggering inflammation which recruits immune effector cells to the site of infection. These conditions theoretically synergize with immune checkpoint blockade (ICB), which aids in establishing and maintaining tumor-infiltrating CD8 T cells. However, clinical data directly confirming synergy between OV and ICB therapy is limited despite ICB becoming the standard of care for several cancer types. It has been shown that viral immunodominance may limit antitumor T-cell priming and cause the attrition of tumor-specific T cells, limiting long-term therapeutic efficacy. To overcome these barriers, precise incorporation of virally expressed or exogenously administered tumor-associated antigens (TAAs) can synchronize the expansion of both antiviral and antitumor T cells, creating optimal conditions for ICB treatment. This tripartite approach leverages our understanding of antiviral immunity to efficiently expand subdominant antitumor T cells in vivo. In this review, we dissect the fundamental paradigm of immunovirotherapy regarding antiviral inflammation and TAAs, followed by relevant combinatorial strategies employed in preclinical and clinical settings for the treatment of solid tumors.