Head and neck squamous cell carcinoma (HNSCC) is characterized by frequent recurrence and poor survival, highlighting the need for reliable biomarkers for risk stratification and therapeutic guidance. Folate-mediated one-carbon metabolism has been linked to tumor development; however, its prognostic and immunological relevance in HNSCC remains unclear. Using The Cancer Genome Atlas (TCGA) transcriptomic data, we developed and validated a folate metabolism–related gene signature (FMRGₛcore). An 11-gene model constructed by least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression effectively stratified patients into distinct survival groups and served as an independent prognostic factor. A nomogram integrating FMRGₛcore with clinical variables demonstrated favorable predictive performance. Functional enrichment analyses revealed activation of oncogenic pathways in high-risk tumors. Immune deconvolution indicated that elevated FMRGₛcore was associated with reduced anti-tumor immune infiltration, increased macrophage-related signals, and an immunosuppressive tumor microenvironment. Drug response prediction suggested higher estimated IC 50 values in the high-risk group, showing potential chemoresistance. Mechanistically, CYP27B1 knockdown suppressed malignant phenotypes and enhanced cisplatin sensitivity. Collectively, these findings establish folate metabolism as a metabolic–immune axis in HNSCC and suggest that the FMRGₛcore may serve as a prognostic and therapeutic stratification tool.
Zhang et al. (2026) studied this question.