{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T11:29:08Z","timestamp":1786447748140,"version":"build-2736575974"},"reference-count":116,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82303332"],"award-info":[{"award-number":["82303332"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The global surge in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has necessitated a fundamental shift in clinical management. While patients exhibit favorable prognoses compared to HPV-negative counterparts, balancing oncological cure rates with toxicity reduction remains a critical challenge. This review elucidates the virological mechanisms driven by oncoproteins E6 and E7 and evaluates novel diagnostic biomarkers, emphasizing the utility of liquid biopsy (circulating tumor HPV DNA,ctHPV DNA) and artificial intelligence for dynamic risk stratification. We critically examine current therapeutic controversies, particularly the risks of recurrence associated with unguided treatment de-escalation. Furthermore, the article highlights innovations in precision medicine, including immune reactivation strategies leveraging viral antigens (therapeutic vaccines, adoptive cell therapy) and targeted interventions exploiting metabolic vulnerabilities (PI3K\/Akt\/mTOR pathway) and DNA damage repair defects. 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