Fucosylated N-Glycan Landscape of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive sub-type of breast cancer lacking targeted therapies. Although aberrant N-glycosylation is a hallmark of malignancy, the specific roles of core-fucosylated (CF) and outer arm–fucosylated (OAF) N-glycans in TNBC progression and patient survival remain underexplored. This study utilized multiplexed glycomics by matrix-assisted laser desorption/ionization imaging mass spectrometry to spatially profile 348 N-glycans in 59 TNBC tumors with clinical characteristics including survival data. Spatial analysis revealed distinct localization patterns of CF and OAF isomers within tumor microenvironments. Strikingly, OAF glycans, but not CF, were strongly associated with tumor stage, with expression increasing from stage I to III and then declining in stage IV. Furthermore, 68 N-glycans were significantly associated with survival outcomes; 36 (52%) of these were OAF-modified, including polylactosamine structures previously linked to metastasis in breast cancer. High expression of OAF polylactosamines correlated with poor prognosis and was detectable in early-stage TNBC tumors, underscoring their potential as prognostic biomarkers. Implications: These findings demonstrate that OAF N-glycans are dynamic, structure-specific markers of TNBC progression and survival, and their early detection and strong prognostic value highlight potential utility in patient stratification and personalized therapy.