Identification and analysis of key transcription factors in esophageal squamous cell carcinoma

Over the past decade, transcription factors (TFs) have emerged as key players in various diseases. Immunotherapy has gained traction as an effective treatment, despite resistance to immune checkpoint inhibitors remains a challenge. The regulatory role of TFs in immunotherapy for esophageal squamous cell carcinoma (ESCC) is poorly understood. This study aims to explore the expression of key TFs, predictive significance, and tumor microenvironment (TME) cell infiltration in ESCC. The expression profiles were obtained from Gene Expression Omnibus (GEO) databases, TF gene data were obtained from the Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TTRUST) database. A protein-protein interaction (PPI) network and enrichment analysis elucidated the molecular processes in ESCC. We investigated the TME cell infiltration landscape in a combined ESCC cohort. The relative abundance of cell infiltration was measured using a single-sample gene-set enrichment analysis (ssGSEA). The diagnostic value of hub TFs for ESCC was investigated using ROC analysis. This study found 48 differentially expressed TFs between normal and ESCC tissues and revealed a strong association between EZH2, FOS, KLF4, FOSB, TWIST1, KLF6 and CEBPB. The results suggested that upregulated EZH2, TWIST1, and KLF4 correlated with immunosuppressive cell infiltration (Tregs, MDSCs) and reduced PD-1/PD-L2 checkpoint expression. Downregulated FOSB and CEBPB associated with enhanced NK cell activity. The diagnostic potential of these key transcription factors in ESCC was evaluated through ROC analysis (EZH2, area under the curve [AUC] = 0.95; TWIST1, AUC = 0.85; CEBPB, AUC = 0.84; FOSB, AUC = 0.79; KLF4, AUC = 0.97; FOS, AUC = 0.84; KLF6, AUC = 0.84). Single-cell data confirmed TF expression in tumor cells, macrophages, and T-cell subsets, highlighting their role in TME remodeling. The scRNA-seq analysis revealed the expression of hub TFs in different cell clusters. The study investigated the expression of DETFs associated with patient prognosis and TME cell infiltration in ESCC.