Breast cancer N Glycosylation dysregulation driven by mutations modulates chemotherapy response and macrophage immunosuppression

Metabolic reprogramming plays a key role in breast cancer progression, but its underlying mechanisms and clinical relevance remain poorly understood. This study integrated multi-omics data from 1,086 breast tumors and 99 normal tissues (TCGA/GEO databases) through combined transcriptomic and single-cell sequencing analyses, pioneering the demonstration of the central regulatory role of N-glycosylation biosynthesis. We identified significant activation of this pathway (P < 0.001), which exhibited co-evolutionary dynamics with high-frequency mutations (TP53/PIK3CA) and enriched specific mutations (PKHD1/BRIP1; P < 10⁻⁴). Mechanistically, this may involve endoplasmic reticulum stress-driven upregulation of glycosyltransferases via the XBP1 pathway. Clinically, tumors with elevated N-glycosylation showed enhanced sensitivity to gemcitabine (32% reduction in half-maximal inhibitory concentration (IC₅₀); P < 0.01) but acquired resistance to the PI3K inhibitor AZD6482 (41% increase in IC₅₀; P < 0.001), providing a molecular basis for chemotherapeutic stratification. Analysis of the tumor microenvironment further revealed macrophage-specific overexpression of SRD5A3 (P < 0.001), which activated the IL-12 signaling pathway (FDR = 0.006) to modulate Th1 cell differentiation—uncovering a novel mechanism of metabolic reprogramming-mediated immune evasion. Our work systematically delineates the pivotal role of N-glycosylation within the "metabolism-genome-immune" network, establishing a foundation for personalized therapy and targeted interventions in breast cancer. These findings collectively highlight N-glycosylation as a clinically actionable metabolic hallmark in breast cancer.