Oral squamous cell carcinomas (OSCC) are aggressive malignancies that are often diagnosed at advanced stages in patients and therefore associated with a poor prognosis. Recently, immune checkpoint inhibitors have received regulatory approval for advanced OSCC patients. Although some OSCC patients exhibit remarkable response to immunotherapy, overall response rates remain low. Identifying an early noninvasive biomarker of immunotherapeutic efficacy could therefore have a significant impact in patient selection. In this regard, our laboratory has been investigating the potential of ultrasound (US) with spatially co-registered photoacoustic imaging (PAI) to monitor OSCC progression and potentially predict response to immunotherapy. Using a novel, orthotopic, immunocompetent model of OSCC (RP-MOC1) we have demonstrated the ability of US-PAI to monitor functional vascular changes during OSCC progression. In preliminary studies, we have also observed observed a significant association between early vascular response to immunotherapy detected by US-PAI and long-term treatment outcomes. Based on these exciting preliminary observations, it is our hypothesis that early vascular response to immunotherapy detected by US-PAI can serve as a biomarker of OSCC progression and immunotherapeutic efficacy. To test this hypothesis, we will examine the spatio-temporal correlation between changes in tumor vascularity and T-cell profiles (Aim 1) and evaluate the ability of US-PAI based hemodynamic response to prognosticate OSCC response to immunotherapy (Aim 2). Successful completion of the proposed studies could enable further development of US-PAI as a novel approach to guide patient selection, monitor immunotherapy, and predict outcomes.