HPV-driven metabolic reprogramming promotes T cell exhaustion: targeting immunometabolic barriers with natural products.

BACKGROUND: High-risk human papillomavirus (HR-HPV) infection is the primary driver of cervical cancer. Emerging evidence indicates that the tumor microenvironment (TME) undergoes severe metabolic rewiring, which may accelerate T cell exhaustion (TEX) and impair immune checkpoint blockade (ICB). However, the molecular mechanisms coupling HPV-driven metabolism to T cell dysfunction remain incompletely elucidated. METHODS: This review summarizes immunometabolic interactions in the cervical cancer TME. We examined the metabolic alterations induced by HPV oncoproteins (E6/E7) and how they reshape nutrient availability, lactate accumulation, and lipid peroxidation to drive anti-tumor CD8+ T cell exhaustion. RESULTS: HPV-driven aerobic glycolysis and IDO1-mediated tryptophan catabolism establish severe metabolic barriers, causing nutrient deprivation and histone lactylation in infiltrating lymphocytes. These alterations are associated with persistent mitochondrial stress and ferroptosis, accelerating terminal TEX. In preclinical models, natural products (e.g., curcumin, berberine, quercetin, and artemisinin derivatives) can counteract this immunosuppressive rewiring by targeting checkpoints such as HIF-1α, PKM2, and AMPK; however, direct evidence of CD8+ tumor-infiltrating lymphocyte rescue in HPV-specific immune-competent systems remains limited, largely inferred from other tumor types. Nanomedicine delivery may further enhance the bioavailability and targeting of these herbal components. CONCLUSION: HPV-induced metabolic reprogramming is proposed to act as a fundamental checkpoint driving T cell exhaustion in cervical cancer. Targeting these immunometabolic barriers using natural compounds, particularly via nanomedicine-based delivery strategies, represents a promising but still largely preclinical avenue to synergize with conventional immunotherapies and potentially overcome resistance.