Infiltration of immunosuppressive M2-programmed macrophages shapes the tumor microenvironment (TME) and is correlated with poor clinical prognosis in cancer. The combinatorial induction of immunogenic tumor cell death and programming the TME from immunosuppressive to inflammatory by employing dsRNA agonists for the endosomal Toll-like receptor 3 (TLR3) represents an alternative strategy for reinvigorating or inducing anti-tumor immune responses. However, uptake of dsRNA by tumor cells is limited and systemic administration is linked to adverse side effects. While the importance of TLR3 activation for programming M2 macrophages into pro-inflammatory M1 macrophages is known, the immunological responses induced by targeted in vivo delivery of dsRNA-based TLR3 agonists to tumors warrant further investigation. For targeted delivery of TLR3 agonist RIBOXXOL to human and murine glioma cells with expression of oncogenic EGFRvIII, we employed a recently described nanoparticle-like immunoconjugate platform designated “Rapid Inducer of Cellular Inflammation and Apoptosis” (RICIA) comprising mono-biotinylated EGFRvIII-specific single chain antibodies and mono-biotinylated RIBOXXOL conjugated to Neutravidin. In the present study we revealed that RICIA is internalized by glioma cells via EGFRvIII-mediated endocytosis and induces a TLR3-dependent type I interferon response. RICIA treatment promoted a proinflammatory shift in both glioma-macrophage co-cultures and tumors, enhanced the frequency of tumor-infiltrating functional cytotoxic T lymphocytes, induced EGFRvIII neo-epitope antibodies, increased survival time, and in a significant number of cases resulted in long-term tumor clearance associated with immune memory. Delivery platforms for targeted delivery of agonists for endosomal TLRs to tumors hold promise as a potent immune-modulatory treatment for cancer.