Promising Targets and Drugs for Improving Head and Neck Cancer Response to Radiotherapy.

Head and neck cancers, particularly Head and Neck Squamous Cell Carcinoma (HNSCC), encompass a diverse group of malignancies with intricate cellular landscapes. The Tumor Microenvironment (TME) is characterized by constant communication between cancer cells and their surrounding cells. Stromal components, immune infiltrates, and Extracellular Matrix (ECM) elements all play crucial roles in this process. These dialogues shape tumor behavior, spread, and treatment resistance. At the molecular level, DNA Damage Response (DDR) by tumoral cells can reduce cell elimination via Ionizing Radiation (IR). Human Papillomavirus (HPV) infection, in some cases, further complicates the picture. Recent findings highlight how these molecular responses, as well as immune modulation, remodeling cell metabolism, enhanced growth factors, and hypoxia in TME, can influence tumor responses to IR. These findings may lead to strategies for radiosensitizing head and neck cancers. Unraveling these interactions is key to developing more effective treatments. This review focuses on different mechanisms of radioresistance in head and neck cancers. Then, we provide an overview of different targets and potential adjuvants or drugs for radiosensitization of these malignancies.