Single-cell and spatial transcriptomics reveal SPRR2A+ epithelial-MMP1+ fibroblast interactions as key drivers of Esophageal Squamous Cell Carcinoma progression.

Esophageal squamous-cell carcinoma is a highly prevalent and lethal malignancy, and its tumor ecosystem is complex and poorly understood; therefore, how malignant epithelial states cooperate with stromal fibroblasts to drive tumor progression remains unclear. Here, we constructed a comprehensive single-cell atlas of primary ESCC tumors, which enabled the subsequent identification of thirteen epithelial subpopulations and seven fibroblast subtypes with distinct functional roles and spatial niches. Further trajectory analysis revealed that progenitor-like PLA2G2A+ fibroblasts differentiate hierarchically into tumor-promoting ACTA2+ and MMP1+ subtypes. Notably, SPRR2A+ epithelial cells and MMP1+ fibroblasts exhibited pronounced spatial co-localization, which may imply reciprocal signaling via TGFB1 and IL6, contributing to the observed extracellular matrix remodeling and malignant behavior. Moreover, functional experiments confirmed that SPRR2A promotes ESCC cell migration and invasion. Altogether, our study characterizes a coordinated epithelial-fibroblast corsstalk and a defined fibroblast differentiation hierarchy, offering new mechanistic insights into the ESCC pro-tumorigenic niche.