Critical Interactions between Immunogenic Cancer Cell Death, Oncolytic Viruses, and the Immune System Define the Rational Design of Combination Immunotherapies

Oncolytic viruses (OVs) are multimodal cancer therapeutics, with one of their dominant mechanisms being in situ vaccination. There is a growing consensus that optimal cancer therapies should generate robust tumor-specific immune responses. Immunogenic cell death (ICD) is a paradigm of cellular demise culminating in the spatiotemporal release of danger-associated molecular patterns that induce potent anticancer immunity. Alongside traditional ICD inducers like anthracycline chemotherapeutics and radiation, OVs have emerged as novel members of this class of therapeutics. OVs replicate in cancers and release tumor Ags, which are perceived as dangerous because of simultaneous expression of pathogen-associated molecular patterns that activate APCs. Therefore, OVs provide the target Ags and danger signals required to induce adaptive immune responses. This review discusses why OVs are attractive candidates for generating ICD, biological barriers limiting their success in the clinic, and groundbreaking strategies to potentiate ICD and antitumor immunity with rationally designed OV-based combination therapies.