Deciphering the Transcription Factor-Dominated Ecosystem During Esophageal Squamous Cell Carcinoma Progression at the Single-Cell Level

Esophageal squamous cell carcinoma (ESCC) progression involves dynamic cellular state transitions and tumor microenvironment remodeling, accompanied by extensive transcriptional regulation reprogramming. Here, we systematically mapped the TF-mediated regulatory landscape underlying ESCC progression at single-cell resolution by integrating stage-specific ESCC single-cell transcriptomic datasets comprising over 200,000 cells with TF–target interaction networks. Using a random walk algorithm combined with hypergeometric testing, we identified malignant progression-associated TFs (mpTFs) across multiple cell types and disease stages. Our analysis revealed extensive stage-dependent regulatory remodeling during ESCC progression. TCF4 was identified as an early-stage regulator associated with epithelial–mesenchymal transition activation and malignant invasive phenotypes. In immune lineages, BATF and IRF4 exhibited trajectory-associated activation during CD4+ T-cell differentiation and CD8+ T-cell exhaustion, suggesting critical roles in immunosuppressive T-cell state transitions. Additionally, mpTF-mediated remodeling of M2 macrophage subpopulations contributed to immunosuppressive tumor microenvironment formation during advanced ESCC progression. We further identified prognosis-associated cell-type-specific and shared mpTFs, including TFAP2C, which was associated with stabilized fibroblast and monocyte functional states and a less aggressive tumor microenvironment phenotype. Collectively, this study provides a comprehensive single-cell atlas of TF-mediated regulatory programs during ESCC progression and offers potential therapeutic targets for precision oncology.