Targeting metabolic reprogramming in HPV-associated oral squamous cell carcinoma: current advances, challenges, and clinical prospects.

Human papillomavirus (HPV)-associated oral squamous cell carcinoma (OSCC) is increasingly investigated as a potentially distinct subset of head and neck cancers with unique molecular features. In contrast to HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), which demonstrates a well-established favorable prognosis, the prognostic significance of HPV in OSCC remains inconsistent and continues to be actively investigated. HPV oncoproteins E6 and E7 are known to induce metabolic rewiring in HPV-driven cancers and are suggested to play a similar role in OSCC, influencing glycolysis, mitochondrial function, and nutrient utilization to support tumor proliferation, survival, and immune evasion. This metabolic reprogramming also contributes to therapeutic resistance, potentially reducing the efficacy of chemoradiation and immunotherapy in subsets of patients. This review synthesizes current evidence from molecular, metabolic, preclinical, and translational studies examining HPV-driven metabolic alterations, incorporating recent findings from both OSCC and broader HPV-associated head and neck cancer (HNSCC) models. It evaluates therapeutic strategies targeting glycolysis, mitochondrial metabolism, metabolic regulators, and drug repurposing approaches. Emerging studies suggest that glycolytic inhibition, mitochondrial modulation, and repurposed agents such as metformin and dichloroacetate (DCA) may suppress tumor growth and enhance therapeutic sensitivity in HPV-positive models. Metabolic crosstalk between tumor cells, stromal components, and immune infiltrates highlights the potential of metabolic targeting to influence both cancer cell survival and antitumor immunity. However, several challenges remain, including tumor metabolic heterogeneity, systemic toxicity of metabolic inhibitors, lack of predictive biomarkers, translational gaps between preclinical models and clinical outcomes, and limited HPV-positive OSCC-specific clinical data. Targeting metabolic reprogramming, therefore, may represent a promising, though still evolving, therapeutic strategy. Advancing this approach may require a biomarker-guided patient stratification and rational combination strategies. Overall, this review provides an integrated overview of HPV-driven metabolic alterations and current therapeutic progress while emphasizing the need for clinically grounded and mechanistically informed translational research.