GALNT1 emerges as a potential therapeutic target in breast cancer.

[PURPOSE] GALNT1, a key enzyme mediating O-GalNAc glycosylation, has not been fully characterized in the tumor microenvironment. This study aimed to investigate its expression pattern, molecular mechanisms, and clinical relevance in breast cancer.

[METHODS] Public datasets (TCGA, GEO, CPTAC) and single-cell transcriptomic data were integrated to analyze GALNT1 expression across cancer types and at the single-cell resolution. The expression and subcellular localization of GALNT1 in breast cancer were verified using qRT-PCR, Western blot, and immunofluorescence staining. Functional assays were conducted to assess its effects on cell proliferation, migration, and O-glycosylation, while CCK-8 assays were used to evaluate sensitivity to bortezomib.

[RESULTS] GALNT1 was significantly upregulated in primary breast cancer as well as multiple other malignancies. In vitro experiments demonstrated that GALNT1 promoted breast cancer cell proliferation, migration, and O-glycosylation. Immunofluorescence staining revealed widespread GALNT1 expression in tumor epithelial cells and cancer-associated fibroblasts (CAFs), with colocalization to the Tn antigen. Notably, GALNT1-mediated O-glycosylation was associated with resistance to bortezomib. High GALNT1 expression correlated with increased infiltration of CAFs and M2 macrophages, and reduced CD8⁺ T cell infiltration. Single-cell transcriptomic analysis further confirmed CAF-specific enrichment and elevated epithelial-mesenchymal transition (EMT) scores.

[CONCLUSIONS] GALNT1 is highly expressed in breast cancer, where it promotes tumor progression, bortezomib resistance through O-glycosylation, and immune microenvironment remodeling. The data imply that GALNT1 could represent a novel therapeutic candidate in breast cancer.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s00432-026-06448-2.