On Day 15, animals were rechallenged with additional B16-F10 cells implanted on the opposite side.<h4>Results</h4>We demonstrated that TTX-RIGA-miR21 was able to induce miRNA-21-dependent RIG-I signaling and apoptosis in melanoma cells, inhibit tumor growth, and induce immunity against tumor rechallenge in an animal model.<h4>Conclusions</h4>Our template-driven approach brings RIG-I closer to becoming a clinically relevant target in oncology by specifically activating immune responses within tumor cells through systemic RIG-I agonist delivery. This evidence concerns the gene RIGI and melanoma.