Molecular biology of radiation response and resistance

Locoregional failure remains a major barrier to cure in head and neck squamous cell carcinoma (HNSCC). Radiotherapy dosing remains largely dictated by anatomy, despite clear biological determinants of radiosensitivity. This review synthesises recent clinical and molecular evidence defining radioresistance and the emerging tools to guide more personalised radiotherapy.

HPV status remains the archetype for intrinsic radiosensitivity and points to actionable vulnerabilities in TP53 -mutant disease. Dose escalation trials have not improved locoregional control, focusing attention on radiosensitisers, with ATR, ATM and DNA-PK inhibition demonstrating promise. DNA damage response inhibition is often limited by achievable exposure and toxicity, emphasising biomarker-guided scheduling and rational combinations. Pathway-level transcriptomic and genomic analyses suggest shared resistance programmes despite heterogeneous upstream drivers, while longitudinal multiomics aims to link baseline risk with on-treatment adaptation.

Biology-guided stratification could personalise radiotherapy indication, dose/fractionation and systemic partnering in HNSCC. Prospective validation of clinical assays and trial designs capturing dynamic resistance are now key priorities.