In situ immunization (ISI) has emerged as a promising approach to bolster early phases of the cancer immunity cycle through improved T-cell priming. One class of ISI agents, oncolytic viruses (OV), has demonstrated clinical activity, but overall benefit remains limited. Mounting evidence suggests that due to their inherent vulnerability to antiviral effects of type I IFN, OVs have limited activity in solid tumors expressing stimulator of interferon genes (STING) and/or retinoic acid-inducible gene I (RIG-I). Here, using a combination of pharmacologic, genetic, and in vivo approaches, we demonstrate that VAX014, a bacterial minicell-based oncolytic ISI agent, activates both STING and RIG-I and leverages this activity to work best in STING-positive and/or RIG-I-positive tumors. Intratumoral treatment of established syngeneic tumors expressing STING and RIG-I with VAX014 resulted in 100% tumor clearance in two mouse models. Antitumor activity of VAX014 was shown to be dependent on both tumor-intrinsic STING and RIG-I with additive activity stemming from host-intrinsic STING. Analysis of human solid tumor datasets demonstrated STING and RIG-I co-expression is prevalent in solid tumors and associates with clinical benefit in many indications, particularly those most amenable to intratumoral administration. These collective findings differentiate VAX014 from OVs by elucidating the ability of this agent to elicit antitumor activity in STING-positive and/or RIG-I-positive solid tumors and provide evidence that STING/RIG-I agonism is part of VAX014's mechanism of action. Taken together, this work supports the ongoing clinical investigation of VAX014 treatment as an alternative to OV therapy in patients with solid tumors.