GALNT7 stratifies dMMR/MSI colorectal cancer into distinct molecular subsets associated with prognosis and PD-L1 expression

Colorectal cancer (CRC) with deficient mismatch-repair (dMMR)/microsatellite instability (MSI) constitutes a distinct clinicopathological and immunological subtype, characterized by high sensitivity to immune checkpoint inhibitors. However, prognosis and therapeutic response vary considerably among dMMR/MSI CRCs, underscoring the need for molecular markers to refine patient stratification. In this study, we systematically investigated cancer-cell-intrinsic expression profiles of 188 glycosyltransferase genes by integrating single-cell, bulk, and cell line RNA-seq datasets. This approach identified five glycosyltransferases, including GALNT7, whose expression differed consistently according to MSI status. The clinical and prognostic relevance of these glycosyltransferases was further analyzed across large-scale transcriptomic, proteomic, and immunohistochemistry cohorts, comprising 662 dMMR/MSI and 3,483 proficient mismatch-repair (pMMR)/microsatellite stable (MSS) CRCs. A five-gene glycosyltransferase signature effectively distinguished MSI from MSS CRCs across 18 datasets. Among the five genes, GALNT7 expression was robustly associated with favorable prognosis in four independent transcriptomic and immunohistochemistry cohorts of dMMR/MSI CRCs, while showing little or no prognostic impact in pMMR/MSS CRCs. Notably, GALNT7 expression was inversely correlated with PD-L1 expression at both the mRNA and protein levels in multiple datasets exclusively within dMMR/MSI CRCs, but not in pMMR/MSS CRCs. Functional assays and lectin microarray analysis using MSI CRC cell lines revealed that GALNT7 knockdown enhanced IFNγ-induced PD-L1 expression without altering cell surface glycosylation. In conclusion, GALNT7 expression stratified dMMR/MSI CRCs into distinct subsets with differential tumor cell PD-L1 expression and diverse survival outcomes, highlighting its potential as a prognostic biomarker to guide treatment strategies.