Both targeted therapies and immunotherapies are now at the forefront of personalized cancer medicine. Aberrant signaling of the epidermal growth factor receptor (EGFR) plays an integral role in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC), making it a compelling drug target. In addition, it is well established that natural killer (NK) cells possess natural antitumor activity and can mediate antibody dependent cellular cytotoxicity (ADCC) upon binding with monoclonal antibodies, such as the EGFR inhibitor cetuximab. However, the presence of drug resistance and/or immune evasion is a major obstacle to progress in this field. In this research project, we hypothesize that increasing the NK cell activity by cetuximab in combination with targeting of NK cell immune checkpoint molecules can synergistically generate an immune mediated elimination of HNSCC cells that are resistant to treatment with cetuximab alone. Importantly, we will investigate the role of human papilloma virus (HPV), as HPV positive HNSCC patients represent a biologically distinct group. By characterizing NK cell functionality and, by extension, the whole immune checkpoint profile in HNSCC, we aim to rationally design new combination strategies to overcome cetuximab resistance, with the ultimate goal to improve the prognosis and life quality of HNSCC patients. Hereby, we will focus on HPV status and the hypoxic microenvironment as important mediators of treatment response.