Epigenetic Regulation of NKT-Cell-Related Gene Signatures and Prognostic Implications in Oropharyngeal Squamous Cell Carcinoma

<h4>Background</h4>Oropharyngeal squamous cell carcinoma (OPSCC) is a major subtype of head and neck cancer, with prognosis increasingly influenced by the tumour immune microenvironment. Although immune checkpoint inhibitors have improved outcomes for some patients, reliable predictive biomarkers remain limited.<h4>Methods</h4>This study aimed to investigate the prognostic relevance and epigenetic regulation of natural killer T (NKT)-cell-related gene signatures in OPSCC. Clinicopathological and transcriptomic data from 81 OPSCC patients were analysed using single-sample gene set enrichment analysis (ssGSEA) to evaluate immune-related gene set enrichment scores. Associations with overall survival and clinical features were assessed, and candidate prognostic genes were further explored through expression, methylation, and network analyses.<h4>Results</h4>High NKT cell differentiation enrichment scores were significantly associated with improved survival and favourable clinical features. Gene-level analyses identified ITK, ZNF683, and ATF2 as key prognostic markers linked to T-cell signalling and epigenetic regulation. Methylation profiling revealed hypermethylation of ITK and hypomethylation of ZNF683 in tumour tissues, suggesting an epigenetic basis for altered gene expression.<h4>Conclusions</h4>These findings highlight NKT cell differentiation as a strong prognostic indicator in OPSCC and support further exploration of epigenetic-immunologic interactions as potential therapeutic targets.