Modern genomics technologies have dramatically transformed cancer research and clinical oncology by enabling molecular classification and targeted treatment of tumors. However, most patients lack treatable oncogenic drivers like mutant EGFR. Classic cytotoxic agents therefore remain the therapeutic backbone in most tumor types including squamous cell carcinomas of the lung and the upper aerodigestive tract. The more recently introduced immunotherapeutics aim to engage the patients’ immune system for anti-tumor attack and can further improve patient survival. Nevertheless, prognosis in these entities is still mainly limited by insufficient response and relapse of resistant disease. Our research aims to address this unmet clinical need by 1) studying the causal molecular determinants of resistance evolution in pre-clinical models and tissue samples using functional genomics and computational biology and by 2) assessing compounds that may promote anti-tumor immunity via enhanced tumor cell-intrinsic inflammatory signaling. Our objective in unraveling these molecular mechanisms is to define novel combinatorial therapeutic strategies that may ultimately help to improve treatment of cancer patients.