Proton therapy has gained popularity for its ability to precisely deposit energy at a specific depth, allowing for higher tumor doses while minimizing radiation exposure to surrounding healthy tissue. This advantage is particularly relevant for head and neck squamous cell carcinoma (HNSCC), the seventh most common cancer globally, where radiotherapy is challenging due to the tumor’s location near critical organs. Despite advances in conventional photon-based radiotherapy, treatments still expose nearby critical organs, often resulting in severe side effects that significantly impact patients’ quality of life. However, robust clinical evidence supporting the superiority of proton therapy for HNSCC remains limited, partly due to the tumor’s heterogeneity and variations in treatment response driven by intrinsic biological factors and the tumor microenvironment. Furthermore, differences in energy deposition at the molecular level between protons and photons may influence DNA repair mechanisms, potentially affecting treatment efficacy in tumors with DNA repair deficiencies. Understanding these variations in biological effects is essential for improving HNSCC patient selection for proton and photon therapy and optimizing personalized radiotherapy strategies....