Our proposed P01 Program consists of three well-integrated projects from a team that has worked closely over the last seven years, completing, and publishing numerous collaborative projects. This P01 application is a natural extension of these concerted efforts and will leverage the complementary expertise of this diverse group of investigators with extensive clinical and basic science experience. The three synergistic P01 Projects are designed to achieve a fully coordinated understanding of how multiple factors in the tumor microenvironment contribute to ICI therapy resistance and guide our efforts to disrupt those key drivers in head and neck squamous cell carcinoma. Ultimately, our studies will facilitate the early identification of those patients who are most likely to develop resistance to ICI therapy and will inform the design of new clinical strategies to more effectively, treat this patient subset.