Therapeutic resistance in HPV-positive oropharyngeal squamous cell carcinoma: molecular mechanisms, clinical challenges, and precision strategies.

Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) exhibits exceptional sensitivity to chemoradiotherapy, with 5-year overall survival exceeding 80%, thereby providing a compelling rationale for treatment de-escalation. However, 15%-20% of patients develop therapeutic resistance and locoregional recurrence, resulting in markedly inferior outcomes. This Review systematically dissects the molecular architecture of treatment resistance in HPV-positive OPSCC, with particular emphasis on mechanisms conferring resistance to radiotherapy, platinum-based chemotherapy, and EGFR-targeted therapy (cetuximab). We delineate core drivers - aberrant DNA damage response (DDR) signaling, epigenetic reprogramming, cancer stem cell (CSC) plasticity, and non-coding RNA networks-and pinpoint actionable vulnerabilities. The contributions and limitations of patient-derived organoids, genetically engineered mouse models, and pivotal clinical trials (notably RTOG 1016) are critically appraised. We address persistent controversies, including the complex relationship between de-escalation and resistance, and highlight the lack of integrative resistance biomarkers. Finally, we propose a roadmap to bridge translational gaps and accelerate the development of precision strategies that circumvent resistance.