ZNF750 suppresses esophageal squamous cell carcinoma by maintaining epithelial barrier–driven mucosal immune homeostasis

Recent studies have shown that zinc finger protein 750 (ZNF750), a key tumor suppressor in esophageal squamous cell carcinoma (ESCC), is associated with defective epithelial differentiation. At the same time, mucosal immune dysfunction is increasingly recognized as a key factor in the development of ESCC. Exploring the role of ZNF750 in regulating the mucosal immune microenvironment provides a new perspective on its tumor suppression mechanism. By integrating analyses across multiple platforms, including bulk transcriptomics (TCGA, GTEx, GEO), and single-cell RNA sequencing (scRNA-seq), we demonstrate that ZNF750 is significantly downregulated in ESCC, with high expression serving as an independent prognostic marker for longer survival. Mechanistically, ZNF750 suppresses ESCC progression by maintaining epithelial barrier–driven mucosal immune homeostasis. WGCNA analyses indicate that ZNF750-high tumors are enriched in mucosal immune response and antimicrobial defense pathways. Experimental validation reveals that ZNF750 positively regulates DEFB4A (human beta-defensin-2), a key antimicrobial peptide. In addition, ZNF750 fosters an anti-tumor immune environment by recruiting neutrophils and suppressing pro-tumor M2 macrophages, a finding corroborated by clinical validation showing that high ZNF750 expression correlates with elevated neutrophil infiltration. Clinical validation confirms that high ZNF750 expression correlates with elevated neutrophil infiltration. Additionally, ZNF750 expression is linked to a healthy mucosal microbiota and the exclusion of pro-carcinogenic bacteria. Single-cell analysis shows that ZNF750-expressing epithelial cells maintain barrier integrity and coordinate immune surveillance through MHC-I/II signaling. Loss of ZNF750 may drive mucosal immune dysregulation, where the immune network is replaced by a pre-fibrotic immunosuppressive niche dominated by cancer-associated fibroblasts (CAFs). Collectively, our findings identify ZNF750 as a key molecular link between epithelial barrier integrity and mucosal immune surveillance in ESCC, highlighting restoration of ZNF750-mediated barrier immunity as a potential therapeutic strategy for ESCC.