Given that the vast majority of the global population has either been vaccinated against or exposed to SARS-CoV-2, we hypothesized that pre-existing antiviral immunity could be locally leveraged to enhance intratumoral immune responses.<h4>Methods</h4>To test this concept, we evaluated the therapeutic efficacy of intratumoral SARS-CoV-2 vaccination in the B16F10 murine melanoma model using two SARS-CoV-2 vaccine platforms: pVAX-SARS-S, a DNA vaccine encoding the spike protein S1 subunit and rAd-SARS2-S1/CD40L, a recombinant adenovirus expressing a secreted S1-CD40L fusion protein. This evidence concerns the gene CD40LG and melanoma.