Integrated multi-omics and single-cell analysis of galectins and immune associations in triple-negative breast cancer

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. Galectins, a family of β-galactoside-binding lectins, have emerged as important mediators of tumor-immune interactions, but their cell-type-specific expression patterns and functional roles within the tumor microenvironment of TNBC remain poorly defined. METHODS: We integrated bulk transcriptomic and genomic data from FUSCC (n = 465) and TCGA (n = 161) TNBC cohorts with single-cell RNA sequencing data from 26 treatment-naïve patients. We systematically assessed galectin expression, genomic alterations, prognostic significance, associations with immune checkpoints and immune infiltration, and cell-type-specific patterns linked to immune contexts and therapeutic response. RESULTS: Galectin family members showed broad dysregulation in TNBC, with recurrent copy number alterations contributing to transcriptional heterogeneity. At the bulk level, LGALS2 was associated with favorable survival, while LGALS3 predicted poor prognosis. Several galectins, including LGALS2, LGALS9, and LGALS10, exhibited positive correlations with immune checkpoint expression and enriched immune infiltration, particularly involving CD8⁺ T cells and tumor-infiltrating lymphocytes. Single-cell analysis revealed distinct galectin expression across malignant, immune, and stromal compartments, suggesting heterogeneous transcriptomically inferred immune contexts. Galectin expression also differed by treatment response: pathological complete response (pCR) to neoadjuvant chemo-immunotherapy was associated with higher LGALS3 and lower LGALS2, LGALS8, and LGALS9, while pCR to chemotherapy was linked to higher LGALS9 and lower LGALS1. CONCLUSIONS: Our study comprehensively characterizes galectin family members in TNBC, revealing their prognostic significance and association with tumor microenvironment and treatment response, and highlighting the clinical and translational relevance of galectins as candidate biomarkers and hypothesis-generating molecules for future mechanistic studies.