A Single-cell and Spatially Resolved Cell Atlas of Human Esophageal Squamous Cell Carcinoma

Tumor heterogeneity and the suppressive microenvironment are key challenges that limit the effectiveness of cancer treatment. In this study, we systematically elucidated the molecular characteristics and mechanisms underlying the suppressive immune microenvironment using a combination of single-cell RNA sequencing, spatial transcriptomics, and metabolomics for a series of human esophageal squamous cell carcinoma and matched non-tumor tissues. We found that COL17A1+ epithelial cells exhibited greater malignancy, characterized by the accumulation of triglycerides and phosphocholine. We also identified a tumor-specific POSTN+ fibroblast subgroup. We identified a unique epithelial-fibroblast niche with low infiltration of effector immune cells and substantial lipid enrichment, composed of POSTN+ fibroblasts and COL17A1+ epithelial cells, in which their crosstalk contributed to tumor progression. We confirmed that the INHBA/TP63 axis played a key role in mediating the regulation of COL17A1+ tumor cells by POSTN+ fibroblasts. Our findings provide new insights into the characteristics of the tumor microenvironment and the crosstalk between tumor cells and fibroblasts, offering valuable multi-omics data for elucidating tumor progression mechanisms.