Squamous cell carcinoma of the head and neck is a significant cause of cancer mortality and morbidity, affecting approximately 900,000 individuals every year and accounting for 400,000 cancer deaths per year worldwide. The clinical landscape of head and neck cancer is evolving rapidly, specifically with respect to newly developed treatments using immunotherapy and immune checkpoint inhibitors (ICI). Nevertheless, a significant fraction of patients fails to respond to this treatment due to mechanisms of resistance that enable the survival and proliferation of tumor cells. We will focus our research in this programmatic effort on the inflammo-metabolic evolution of resistance to ICI treatment as cells transform from normal to malignant through their interactions with the surrounding tumor microenvironment. Targeted therapies designed to inhibit tumor-intrinsic signaling do not account for the influences of the microenvironment, and the recent success of immunotherapy illustrates the importance of the local microenvironment in tumor growth, progression, and resistance. Our ongoing studies have revealed that the responders to ICI and non-responders have different inflammatory and metabolic profiles. We hypothesize that the acquisition of resistance is driven by a complex interplay of inflammatory and metabolic communication signals that occurs in the microenvironment and promotes the resistant profile. The interactions between keratinocytes, stromal, and immune cells in the tumor microenvironment have been vastly underexplored during the tumor’s formative development.