Integrated analysis of glutamine metabolism and immune microenvironment identifies GOT2 as a prognostic gene in head and neck squamous cell carcinoma

Glutamine metabolism plays a key role in cancer initiation and progression. This study aims to explore the independent and interactive roles of glutamine metabolism-related genes and immune characteristic in head and neck squamous cell carcinoma (HNSCC). Clinical and gene expression data from HNSCC patients were downloaded from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA). A comprehensive evaluation of 21 glutamine metabolism-related genes in HNSCC tissues was conducted. A risk model based on glutamine metabolism-related genes was constructed using Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. The association between glutamine metabolism-related genes and immune infiltration was assessed using the Estimation of STromal and Immune cells in MAlignant Tumors using Expression data (ESTIMATE) method. The expression levels of the hub gene were verified in vitro models. Four glutamine metabolism-related genes (GOT2, FAH, LAT, and SLC7A11) were identified for constructing a risk score model for HNSCC patients. High expression levels of GOT2 were identified as a poor prognostic factor in HNSCC, as demonstrated by Kaplan-Meier analysis (HR:1.006, p < 0.001). Patients with a low-risk score exhibited higher ESTIMATE scores and Immune Scores compared to those with a high-risk score. GOT2 emerged as a hub gene associated with the survival of HNSCC patients. In vitro functional experiments demonstrated that downregulation of GOT2 expression suppresses proliferation, invasion, and metastasis. In conclusions, we developed and validated a prognostic risk scoring system based on four glutamine metabolism-associated genes, which demonstrated robust predictive capacity for clinical outcomes and immune infiltration patterns in HNSCC. Mechanistically, GOT2 emerged as a central regulator interfacing with the immunosuppressive tumor microenvironment, potentially driving oncogenesis through dual metabolic-immune reprogramming. These findings highlight GOT2 as a novel therapeutic target, offering a promising strategy to overcome immunotherapy resistance in HNSCC.