Treatment of head and neck squamous cell carcinomas (HNSCC) remains challenging with regards to radioresistance, particularly of Human Papilloma Virus (HPV)-negative tumors. Several new approaches are currently under pre-clinical and clinical investigation. Combination of radiotherapy (RT) and kinase inhibitors of the DNA damage repair system (DDRi), targeting Ataxia Telangiectasia Mutated (ATM) or ATM and Rad3-related (ATR), are promising, but the consequences on tumor cell phenotype are still scarce. We used AZD0156, an ATM inhibitor, and VE-822, an ATR inhibitor, in combination with normo-fractionated RT to treat two HPV-positive and two HPV-negative HNSCC cell lines. Generally, an effective reduction of clonogenicity was detected in tumor cells treated with a combination of RT + DDRi. Inhibiting ATM in combination with RT changed the cellular morphology, enhanced β-Gal activity and intensified secretion of senescence-associated cytokines. As senescent cells are naturally targeted by NK cells, we next analyzed the release of the cytokines IL-6 and IL-8 and found them to be differently regulated by the inhibitors. In co-culture with NK cells, an upregulation of activation markers on NK cells was observed, particularly after contact with RT + ATMi-treated HPV-negative HNSCC cells. We conclude that ATM inhibitor-related induction of senescence in HNSCC cells shapes the tumor micro-environment in way that NK cell phenotype is changed.