In head and neck cancer (HNC) and many other solid tumor types immune checkpoint inhibitors (ICIs) approaches are effective in just a subset of patients (e.g. 15-20%). Our in-depth analysis of multiple smoking- related malignancies has revealed that tumor derived factors, both genetic and metabolic, may be far more important in dictating a permissive tumor immune microenviroment (TIME) than previously appreciated. As we continue to move forward with a plethora of new clinical trials trying different regimens of ICIs layered upon standard of care chemotherapy and/or radiation we may very well be missing the mark by not considering more strongly the genomic background and individual cancer biology underpinning the very tumors being treated. We believe the next revolution in immune-oncology is more likely to stem from combination therapy that directly targets the hidden biology of tumors that makes them dodge the immune system rather than discovery of yet another ICI molecule. Specifically, we have accumulated a large body of evidence that points to Nrf2 pathway activation as a major driver of cancer biology and immune escape. This pathway in the context of immune checkpoints holds great theranostic promise for improving ICI outcomes and at the same time for overcoming resistance to orthogonal standard of care chemotherapy and radiation. Here we will link tobacco exposure and Nrf2 across the biological spectrum of HNC by measuring the temporal kinetics of tobacco exposure effects on Nrf2 activation in HNC (Subaim 1.1). Using a layered approach we will measure the level of Nrf2 activation following chronic tobacco exposure and identify downstream drivers of survival to oxidative stress generated by tobacco exposure in selected cell lines (Subaim 1.2). Using established immunodeficient murine models of HNC we will then link tobacco exposure to Nrf2 activation in vivo (Subaim 1.3) and demonstrate that pharmacologic inhibition of Nrf2 can reduce tobacco exposure effects on downstream gene activation. In Aim 2 we will define the mechanisms by which Nrf2 activation regulates TIME. We previously identified one key Nrf2 target, Gpx2 as a driver of a suppressive TIME using human data and murine models of HNC. We will measure immune effects of acute and chronic tobacco exposure as a function of Nrf2 activation and Gpx2 activity (Subaim 2.1) in vitro and using immunocompetent HNC murine models as it relates to functional immunocytes (CD8+ T cells) and suppressor MDSCs (Subaim 2.2). Finally, we will define the impact of tobacco induced Nrf2 activation on immune checkpoint inhibitor (ICI) effectiveness in HNC. We will measure the impact of chronic smoke induced Nrf2 activation on ICI effectiveness in immunocompetent HNC models (Subaim 3.1) and test whether either direct reversal of Nrf2 activity (ML385) or indirect inhibition of downstream effects via the glutaminase-1 (GLS1) inhibitor IACS6274 can restore maximal ICI effectiveness in against HNC tumors (Subaim...