The landscape of B and plasma cells in breast cancer: insights from single-cell and spatial transcriptomics

Abstract Tumor-associated B (TAB) cells and plasma cells are increasingly recognized as key components of the tumor microenvironment; however, their heterogeneity and functional roles in breast cancer remain incompletely understood. Here, by integrating publicly available single-cell RNA (scRNA) sequencing datasets with newly generated scRNA-seq and single-cell BCR sequencing data from 79 samples across 35 patients, we constructed a comprehensive atlas of B and plasma cells in breast cancer. Systematic analyses of transcriptional profiles, clonal expansion, spatial distribution, and cell-cell interactions revealed 21 distinct subsets of TAB cells with substantial functional diversity. Among them, two tumor-enriched populations, CD200+ naïve B cells and ISG15+ atypical memory B cells, exhibited marked clonal expansion and activation signatures. Notably, CD200+ naïve B cells were closely associated with tertiary lymphoid structures, improved clinical outcomes, and enhanced responses to immune checkpoint blockade. Functional validation in multiple murine tumor models demonstrated that CD200+ B cells are essential for optimal anti-tumor immunity and critical for the efficacy of anti-PD-1 therapy. Together, our findings provide a high-resolution landscape of B and plasma cells in breast cancer and highlight CD200+ tumor-associated B cells as promising biomarkers and potential therapeutic targets to improve immunotherapy outcomes.