The information gathered to date on the biological effects of protons versus photons in HNSCC points to the need for additional investigations combining proton radiation with molecular or immune targeted therapy (eg, antiangiogenic VEGF-C, depletion of USP6 [ubiquitin specific peptidase 6], anti-immune checkpoints) to enhance the antitumor effects of proton radiation, with the ultimate goal of improving tumor control while minimizing treatment-related toxicity for patients with HNSCC. This evidence concerns the gene USP6 and head and neck squamous cell carcinoma.