Spatial omics study reveals molecular-cellular dynamics of tumor ecosystem in esophageal squamous-cell carcinoma initiation and progression.

Deciphering the molecular and cellular dynamics during esophageal squamous-cell carcinoma (ESCC) evolution is critical for elucidating the underlying disease mechanisms and devising rational targeted therapeutic strategies. Here, we perform digital spatial profiling on 32 tissue samples from 18 patients across different ESCC stages. At ESCC initiation, tumor cells undergo coordinated regulation of epidermal development and keratinocyte differentiation, accompanied by increased B cells and decreased T cells. In late stages, the phosphatidylinositol 3-kinase-protein kinase B (PI3K/AKT) pathway is continuously upregulated, and tertiary lymphoid structures are dysregulated. We further verify these findings by multiplex immunofluorescence. Notably, the O-GlcNAc transferase gene, activated exclusively in late stages, correlates with poor prognosis, and its knockdown inhibits ESCC cell migration and invasion. In summary, this study unravels ESCC ecosystem evolution mechanisms via spatial omics, providing a roadmap for precision therapeutics.