Single‐Cell and Bulk Transcriptomics Identify GNGT1 ‐High Malignant Epithelial Cells Associated With Immune Suppression in Esophageal Squamous Cell Carcinoma

ABSTRACT

Esophageal squamous cell carcinoma (ESCC) features epithelial heterogeneity and an immunosuppressive microenvironment, yet clinically relevant malignant epithelial states remain poorly defined. We integrated four single‐cell RNA‐sequencing datasets and 10 bulk transcriptomic cohorts totaling 1318 samples, and applied cross‐cohort differential expression, survival analysis, and a machine‐learning framework of 113 algorithm combinations to screen for malignant epithelial cell‐associated biomarkers. GNGT1 was prioritized for its consistent upregulation, prognostic association, and limited prior characterization in ESCC. Across independent cohorts, GNGT1 exhibited favorable diagnostic performance, while high expression correlated with poorer overall survival and more advanced local tumor status. Immune deconvolution consistently linked GNGT1‐high tumors to reduced CD8 ⁺ T‐cell infiltration, lower immune scores, and decreased cytotoxic T‐cell markers. Single‐cell analyses further associated GNGT1‐high epithelial cells with altered epithelial–immune communication involving MIF, prostaglandin, and CXCL signaling, alongside enrichment of epithelial–mesenchymal transition, mTORC1, and proliferative programs; qPCR confirmed elevated GNGT1 expression in ESCC cell lines. This study defines GNGT1 as a marker of an immunosuppressive malignant epithelial state, thereby bridging epithelial heterogeneity with immune remodeling in ESCC. These findings support GNGT1 as a candidate diagnostic, prognostic, and biologically informative biomarker warranting mechanistic and clinical validation.