Stemness and NK-like signatures define a subtype of esophageal squamous cell carcinoma with poor prognosis

To explore the biology of esophageal squamous cell carcinoma (ESCC) and identify new therapeutic opportunities, comprehensive genomic-transcriptomic characterizations of 120 Chinese ESCC patients were performed. Here we show that ESCC can be categorized into differentiated, metabolic, immunogenic and stemness subtypes based on transcriptomics, with each subtype exhibiting unique molecular and histopathological features. The stemness subgroup, with four key signature genes (WFDC2, SFRP1, LGR6 and VWA2), has the poorest prognosis and was associated with downregulated immune activities, a high frequency of EP300 mutation/activation, functional mutation enrichment in Wnt signalling and the highest level of intratumoural heterogeneity. The immune profiling further revealed ESCC tumour cells overexpress NK cell markers XCL1/2 and CD160 as a new immune evasion strategy. Strikingly, XCL1 expression also affects the sensitivity of ESCC cells to common chemotherapy drugs. This study opens up new avenues for ESCC treatment and provides a unique public resource to better understand and treat ESCC.