PROJECT SUMMARY Known risk factors for oral cancers are tobacco and alcohol use and human papillomavirus (HPV) infection. There is a clear interaction between tobacco use and HPV infection. Smokers have a significantly higher rate of persistent oral HPV infection which is a significant risk factor to develop oral cancer. Patients with tobacco- related oral cancers have poor prognosis. Apart from the obvious damage tobacco causes to genomic DNA, cigarette smoke exposure also significantly impacts the immune system. Recently immunotherapy has become a promising therapeutic option in oral cancer. Programmed cell death-1 (PD-1) is one of the clinically significant checkpoint molecules that have been shown to suppress T-cell function upon binding to its ligands, PD-L1 and PD-L2. Nivolumab and pembrolizumab are the two PD-1 inhibitors with the most efficacy and safety data in management of oral cancer. While the detrimental effects of continued tobacco use have been established over the years, the effects of tobacco use in the tumor immune microenvironment (TIME) and immunotherapy efficacy in oral cancers are poorly investigated. In this proposal, we will comprehensively evaluate the tobacco-related effects on the oral cancer ecosystem through integrated multi-omics approaches, identify novel therapeutic agents leveraging the oral cancer-specific TIME, and develop an oral cancer specific web portal to advance the field in tobacco-related cancer research.