Oral squamous cell carcinoma (OSCC) is a devastating epithelial malignancy arising from the mucosa of sites that include the oral tongue, the floor of mouth, and the buccal mucosa. Advanced disease still has a dismal 5-year survival rate of only ~50%, despite advances in surgical and radiation approaches. Immunotherapy, such as PD-1 checkpoint blockade, has shown very promising results in a number of malignancies, but in general, responses are seen only in a minority of the cases. Numerous strategies to enhance endogenous and synthetic immune-mediated rejection of tumors are under intense investigation; however, all face significant challenges pending better understanding of the interface between tumor cells and the immune system within the tumor microenvironment (TME). Areas needing clarity include (1) factors determining tumor sensitivity to immune pressure; (2) factors determining the expression of neoantigens; and (3) factors determining immune cell plasticity and “states” induced within the TME. Our research program has been investigating aspects of the tumor-immune interface. We use primary tumor samples and novel mouse models to understand how to modulate the immune response to treat human OSCC. We are specifically interested in understanding how tumor heterogeneity influences the immune response; how we can induce neoantigens on OSCC for immune targeting; and how we can enhance NK cell function to treat OSCC.