Despite accounting for less than 5% of all skin cancers, the vast majority of skin-cancer related deaths are attributable to melanoma. An emergent ‘targeted’ approach to melanoma treatment involves the use of immune checkpoint inhibitors (e.g., anti PD-1/PD-L1 therapy) that work by bolstering the body’s own antitumor immunity. By harnessing the intrinsic capabilities of the adaptive immune system to recognize self (i.e., ‘non-cancer’) from non-self (i.e., ‘cancer’), such strategies accelerate tumor removal and have the added benefit of potentially establishing long-term cancer immunity. Although, immune checkpoint inhibitors have shown remarkable efficacy in the clinic, a substantial portion of patients fail to respond. While this refractoriness (lack of efficacy, failure to respond) is likely multifactorial, a growing body of evidence is emerging which causally links immune cell failure to disruptions in the body’s major energy producing organelle – the mitochondrion. That said, the scientific community has not yet discovered what causes the immune cell mitochondria to fail. Therefore, this proposal plans to investigate differences in these energy-producing organelles in the context of anti-melanoma immunity. Once these distinguishing characteristics of immune cell mitochondria are identified, it becomes possible to design new drugs that can potentially augment these features. Although the development of new drugs for the clinic does take considerable time, identifying immune-specific drug targets is the necessary first step. The short-term goal of this application is to identify these immune-specific drug targets such that in the long-term patients diagnosed with melanoma can be afforded better, more effective immune therapies. The work described herein has considerable relevance to both current and former military service members, as these individuals are at an increased risk for developing melanoma.