Multi-omics identifies an epithelial-B cell cross-talk that drives functional B cell diversion in breast cancer lymph node metastasis.

Lymph node metastasis is a critical determinant of poor prognosis in breast cancer, yet the functional heterogeneity of B cells and their roles during metastasis remain poorly understood. Through integrated single-cell RNA sequencing of paired primary tumors and metastatic lymph nodes in HR+/HER2- breast cancer, spatial transcriptomics, and in vivo functional models, we systematically mapped B cell states and interactions during metastatic progression. We found that IgA+ plasma cells, which promote tumor progression, were significantly expanded in metastatic lymph nodes, whereas immunostimulatory IgG+ plasma cells predominated in primary tumors. The distinct functional phenotypes of these subsets were validated by in vivo antibody supplementation. Additionally, KLF2+ B cells exhibited divergent functional differentiation between carcinoma and lymph node sites. Functional in vivo assays confirmed that epithelial-derived LPAR2 signaling modulates B cell activation and cytotoxic function, thereby facilitating metastatic progression. We developed a ligand-receptor interaction score that robustly predicted prognosis across independent cohorts. Together, our findings elucidate the spatial and functional reprogramming of B cells in breast cancer metastasis and highlight their potential as therapeutic targets.