Background: Strong inter-individual variation in clinical response to immune checkpoint inhibitors (ICB) including anti-CTLA-4 remains a major challenge, but the molecular pathways that modulate ICB efficacy remain ill defined. Methods: Using CRISPR/Cas9 technology to generate melanoma cells lines that lack nucleic acid receptors or downstream signaling molecules together with available genetically deficient mouse models, we addressed the importance of nucleic acid receptor signaling in both tumor and host cells for the efficacy of anti-CTLA-4 immunotherapy. Results: We demonstrate that anti-CTLA-4 immunotherapy relies on melanoma cell-intrinsic activation of the cytosolic RNA receptor RIG-I (DDx58) but not the DNA sensing adaptor protein STING. Mechanistically, RIG-I signaling induced caspase-3-mediated tumor cell death, cross-presentation of tumor-associated antigen by CD103⁺ dendritic cells, subsequent expansion of tumor antigen-specific CD8⁺ T cells and the accumulation of CD8⁺ T cells within the tumor tissue. These processes were independent of tumor-cell derived type I IFN (IFN-I), but additionally required host STING, MAVS and IFN-I signaling. Consistently, therapeutic targeting of RIG-I with 5’-phosphorylated-RNA in both tumor and non-malignant host cells potently augmented the efficacy of CTLA-4 checkpoint blockade. Conclusions: Our data are consistent with the finding that expression of RIG-I in human melanomas has been associated with clinical benefit to CTLA-4 blockade and identify activation of RIG-I/MAVS signaling in tumors and their microenvironment as a crucial component for checkpoint inhibitor-mediated immunotherapy of cancer. These findings not only nominate tumor intrinsic RIG-I activity as potential biomarker for treatment response to checkpoint inhibitors, but predict that targeting this pathway may serve as a basis for the development of new combined modality approaches to increase the response rate of checkpoint inhibitor-based immunotherapy, particularly in individuals that do not have a sufficient spontaneous antitumor T-cell immune response.