Head and neck cancer (HNC) is the sixth cause of cancer-related death worldwide.\nHead and neck squamous cells carcinoma (HNSCC) is the most frequent subtype of HNC.\nThe development of HNSCC is associated to alcohol consumption, smoking or infection by high-risk\nhuman Papillomavirus (HR-HPV). Although the incidence of cancers associated with alcohol and\ntobacco has diminished, HNSCC associated with HR-HPV has significantly increased in recent years.\nHowever, HPV-positive HNSCC responds well to treatment, which includes surgery followed by\nradiation or chemoradiation therapy. Radiation therapy (RT) is based on ionizing radiation (IR)\nchanging cell physiology. IR can directly interact with deoxyribonucleic acid (DNA) or produce\nreactive oxygen and nitrogen species (RONS), provoking DNA damage. When DNA damage is not\nrepaired, programmed cell death (apoptosis and/or autophagy) is induced. However, cancer cells\ncan acquire resistance to IR avoiding cell death, where reprogramming of energy metabolism has\na critical role and is intimately connected with hypoxia, mitochondrial physiology, oxidative stress\n(OS) and autophagy. This review is focused on the reprogramming of energy metabolism in response\nto RT in HPV-positive and HPV-negative HNSCC, showing their differences in cellular metabolism\nmanagement and the probable direction of treatments for each subtype of HNSCC.
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