Cumulatively, our results suggest that targeting DNA DSB repair via NHEJ (ATM and DNA-Pkcs) or HR (ATR) can exacerbate the impact of photons in radiosensitising HNSCC cell models, and that the combination of DNA-Pkcsi with photons in HPV-negative HNSCC cells that are relatively radioresistant was particularly effective. Here, ATM is linked to head and neck squamous cell carcinoma.