Polio virotherapy provokes MDA5 signaling and CD4 ⁺ T cell help to mediate cancer in situ vaccination

T cell responses are quintessential defensive measures directed against categorically intracellular pathogens. It is thus intuitively obvious that viruses hold unique potential to mediate cancer in situ vaccination, the process whereby endogenous immune responses are provoked to empower antitumor immunity. Numerous attenuated viruses have been derived from diverse virus families and tested as intratumor "cancer virotherapies." However, the mechanistic understanding of how viruses mediate cancer in situ vaccination -including whether such attenuated viruses maintain the capacity to subvert antigen presentation and T cell priming, a common, defining feature of their wild-type precursors that may limit in situ vaccination, as well as the role of innate and adaptive antiviral immune responses in mediating overall therapy benefit-remains largely undefined. In this review, we provide a comprehensive overview of the molecular mechanisms, the unexpected benefit of profound attenuation, and the central role of both innate and adaptive antiviral immune responses in mediating polio virotherapy. In doing so, we aim to highlight the need for unraveling the enormous complexity and depth of virus:host interactions for devising rational strategies to leverage them for cancer immunotherapy.