Identification of a ferroptosis-associated gene signature and the related therapeutic targets in head and neck squamous carcinoma

Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis due to its high rates of recurrence and metastasis. Herein, we designed and validated an individualized ferroptosis-associated gene signature (FGS) and further probed the potential survival mechanisms along with therapeutic targets for HNSCC.The FGS risk score was constructed using stepwise regression analysis and validated in the GSE41613 cohort. Characterization of the tumor microenvironment (TME) in patients with HNSCC, involving immune cells and immunomodulatory genes, was performed to investigate the survival mechanisms and therapeutic targets associated with FGS. To validate the role of FGS in TME, multiplex fluorescent immunohistochemistry (mfIHC) was performed on tissue sections from 55 patients with oral squamous carcinoma.The risk score obtained from FGS showed good predictive power as an independent predictor of overall survival. From the tumor immune dysfunction and exclusion (TIDE) prediction, it was found that patients at low risk may benefit from immunotherapy. Furthermore, FGS was significantly associated with CD276, which was highly expressed in fibroblasts that enriched in angiogenesis and epithelial-mesenchymal transition pathways at a single-cell resolution, suggesting CD276 may play a critical mediator of the immunosuppressive microenvironment. Lastly, we identified ATG5 as a critical gene in FGS. And the immune-bioinformatics analysis combined with experimental validation showed a negative correlation between ATG5 expression and CD8 + T cells.The FGS model provides a novel and effective method to predict the prognosis of patients with HNSCC and their survival can be prolonged through TME-related therapeutic targets.