Identification of core cytotoxic T lymphocyte-related subtypes, establishment of a prognostic model, and analysis tumor microenvironment infiltration in HNSC

Head and neck squamous cell carcinoma (HNSC) is a common and clinically diverse malignancy associated with poor outcomes. Recent evidence suggests that cytotoxic T lymphocyte evasion-related genes (CEGs) are pivotal regulators of tumor immune escape, yet their overall prognostic significance and influence on the tumor microenvironment (TME) in HNSC remain poorly defined. Here, a systematic analysis of 31 CEGs was conducted across TCGA and GEO HNSC datasets to identify molecular subtypes via consensus clustering. A risk score based on this signature was developed, validated in external cohorts, and integrated with clinical data into a nomogram. Associations between the risk score and TME features, immune checkpoints, somatic mutations, cancer stemness indices, and drug sensitivity were comprehensively assessed. The identified molecular subtypes exhibited markedly different immune infiltration patterns and survival outcomes. The developed model enabled effective patient stratification into high- and low-risk groups that differed significantly in overall survival. High-risk patients displayed upregulated immune checkpoint expression and heightened sensitivity to several chemotherapeutic agents. Knockdown of SERPINE1 in HNSC cell lines led to marked inhibition of both proliferation and colony formation. The findings demonstrate the critical involvement of CEGs in HNSC progression and immune modulation, and proposes a novel three-gene signature as a robust prognostic biomarker and potential guide for individualized therapy.