Patients with mucosal melanoma are likely to have poor outcomes with current standard-of-care treatment options. The reasons are multifactorial but include difficulty obtaining wide surgical resection margins given anatomically challenging sites of disease (e.g., near the base of the skull or in the anogenital area) and suboptimal response rates to immunotherapy. This project aims to improve outcomes for mucosal melanoma patients by combining radiation therapy with immunotherapy in the pre-operative setting, while creating a new, multimodality biomarker platform to predict for the likelihood of response. We anticipate that adding pre-operative radiation therapy will help improve immunotherapy response rates by directly killing melanoma cells while also improving the immune system’s ability to recognize and eradicate these cells. Such an improved treatment response may also help a surgeon remove the tumor completely with negative margins while maintaining maximal organ functionality and patient quality of life. In addition, we expect that our longitudinal blood-, tissue- and advanced imaging-based biomarker platform will create a framework to help personalize treatment recommendations for future patients to maximize the likelihood of treatment response and long-term disease control.