Many cancer immunotherapy patients fail to respond or progress after initially experiencing tumor regression. More than 25% of melanomas carry activating mutations in the driver oncogene NRAS. Unlike other genomic variants of melanoma, NRAS mutant patients respond poorly to current immunotherapies and targeted agents; therefore, new therapies are urgently needed. A major gap in knowledge that limits the application of immunotherapy in NRAS mutant cancers is the identification of immunogenic targets selectively expressed by tumor cells and not normal tissues. This proposal seeks to develop new, mechanism-based immunotherapies to target melanoma and other common cancers with specific genetic alterations associated with resistance to current treatments. As part of these studies, new generalizable knowledge will be generated that improves our molecular understanding of how the adaptive immune system can distinguish between normal and transformed tissues.