Human papillomavirus driven head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal squamous cell carcinoma (OPSCC), are characterized by a significant survival advantage over their HPV-negative counterparts. Although the reasons behind this are still not fully elucidated, it is widely accepted that these tumors have a higher response to ionizing radiation that might explain their favorable outcomes. Potential underlying intrinsic mechanisms include impaired DNA repair abilities, differences in activated repopulation-signaling pathways and cell cycle control mechanisms. The role of the microenvironment is increasingly highlighted, particularly tumor oxygenation and the immune response. Recent studies have shown a distinct pattern of intratumoral immune cell infiltrates, according to HPV status, and have suggested that an increased cytotoxic T-cell based antitumor immune response is involved in improved prognosis of patients with HPV-positive OPSCC. These significant milestones, in the understanding of HPV-induced HNSCC, pave the way to new therapeutic opportunities. This article reviews the current evidence on the biological basis of increased radiosensitivity in HPV-positive HNSCC and discusses potential therapeutic implications.
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