Predictors of Radiation Resistance and Novel Radiation Sensitizers in Head and Neck Cancers: Advancing Radiotherapy Efficacy

Radiation resistance in head and neck squamous cell carcinoma (HNSCC), driven by intrinsic and extrinsic factors, poses a significant challenge in radiation oncology. The key contributors are tumor hypoxia, cancer stem cells, cell cycle checkpoint activation, and DNA repair processes (homologous recombination and non-homologous end-joining). Genetic modifications such as TP53 mutations, KRAS mutations, EGFR overexpression, and abnormalities in DNA repair proteins like BRCA1/2 additionally affect radiation sensitivity.

Novel radiosensitizers targeting these pathways demonstrate the potential to overcome resistance. Hypoxia-activated drugs and gold nanoparticles enhance the efficacy of radiotherapy and facilitate targeted distribution. Integrating immunotherapy, especially immune checkpoint inhibitors, with radiation therapy, enhances anti-tumor responses and reduces resistance. Epigenetic alterations, such as DNA methylation and histone acetylation, significantly influence radiation response, with the potential for sensitization through histone deacetylase inhibitors and non-coding RNA regulators. Metabolic changes linked to glucose, lipid, and glutamine metabolism influence radiosensitivity, uncovering new targets for radiosensitization. Human papillomavirus (HPV)-associated malignancies exhibit increased radiosensitivity relative to other tumors due to impaired DNA repair mechanisms and heightened immunogenicity. Furthermore, understanding the interplay between HPV oncoproteins and p53 functionality can enhance treatment strategies for HPV-related cancers. Using DNA damage response inhibitors (PARP, ATM/ATR), cell cycle checkpoint inhibitors (WEE1, CHK1/2), and hypoxia-targeted agents as radiosensitizing strategies exhibit considerable promise. Immunomodulatory approaches, including PD-1 and CTLA-4 inhibitors in conjunction with radiation, enhance anti-tumor immunity.

Future directions emphasize personalized radiation therapy using genetics, sophisticated medication delivery systems, adaptive radiotherapy, and real-time monitoring. These integrated strategies seek to diminish radiation resistance and improve therapeutic efficacy in HNSCC.