Achieving tumor-specific, robust, and durable effector cytotoxic immune responses is key to successful immunotherapy. This has been accomplished with adoptive cell transfer of ex vivo-expanded autologous tumor-infiltrating or engineered T cells, or with immune checkpoint inhibitors, enhancing inherent T cell reactivity. A natural ability to recruit effector responses makes tumor-targeting ('oncolytic') viruses attractive as immunotherapy vehicles. However, most viruses actively block inflammatory and immunogenic events; or, host innate immune responses may prevent immune initiating events in the first place. Moreover, the mechanisms of how virus infection can produce effector responses against host (tumor) neo-antigens are unclear. We are pioneering oncolytic immunotherapy based on poliovirus, which has no specific mechanism to interfere with host immune activation, exhibits lytic cytotoxicity in the presence of an antiviral interferon response and pre-existing immunity, and engages a powerful innate immune sensor implicated in recruiting cytotoxic T cell responses. Central to this approach is a unique confluence of factors that drive tumor-specific viral translation and cytotoxicity.