Abstract

Background Head and neck squamous cell carcinoma (HNSCC) remains a major cause of cancer mortality, and robust biomarkers are needed for prognosis stratification and immuno-oncology research. We investigated coagulation factor II receptor-like 1 (F2RL1) in HNSCC, focusing on expression, clinical outcomes and immune associations. Methods RNA sequencing and clinical follow-up data from The Cancer Genome Atlas head and neck squamous cell carcinoma cohort (TCGA-HNSC) were analysed. Three independent Gene Expression Omnibus (GEO) cohorts (GSE9844, GSE55547 and GSE55548) were used for external confirmation, with preprocessing and differential-expression exports generated using Xiantao Academic. Immune infiltration, functional enrichment and multi-omics annotations were assessed. Experimental validation was performed using reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting and immunohistochemistry (IHC). Results F2RL1 was significantly upregulated in HNSCC and was associated with worse overall survival (OS). Expression differences were consistent across the three GEO cohorts. F2RL1 showed significant associations with immune cell infiltration and immune checkpoint genes, and correlated with DNA methylation features and N6-methyladenosine (m6A) regulators. A nomogram was constructed to estimate 1-, 3- and 5-year OS. Conclusion F2RL1 is reproducibly overexpressed in HNSCC and is linked to adverse outcomes and immune-related features, supporting its potential as a prognostic biomarker and candidate therapeutic target.