Recent large-scale multi-omics studies have characterized the heterogeneity of esophageal squamous cell carcinoma (ESCC), but inconsistent clinical management has hindered the identification of prognostic markers and patient stratification. Here, we conducted genomic and transcriptomic profiling of 203 patients from the ECTOP-2002 study with full clinical information. Mutation in the mucin family, as well as APOBEC signature, were associated with poor prognosis. In contrast, activation of the epithelial-keratinization (EpK) pathway was strongly linked to favorable prognosis and lower post-chemotherapy recurrence rates. Independent validation supported S100A8 + S100A9 complex as a key marker of EpK pathway. Furthermore, we established a prognostic stratification system, FU-ESCC subtyping, which defines three subtypes with distinct molecular and clinical features. The EpK-activated subtype retained characteristics of healthy squamous epithelial cells, showed high expression of the S100A8 + S100A9 complex, and was associated with favorable prognosis. The cancer-associated fibroblast (CAF)-enriched subtype showed elevated FAP and Vimentin expression, abundant CAFs, high proliferative activity, and poor prognosis. The immune-desert subtype was characterized by low immune infiltration, suppressed immune signaling, and similarly poor prognosis. Our study provides a valuable resource and insights to better understand ESCC in the era of precision medicine and targeted therapies.
© 2025. The Author(s).