Bo Xiang, Tao Liu, Duo Xu, Wei Wang
The clinical success of immune checkpoint blockade and adoptive T-cell therapies has cemented a T-cell-centric paradigm in cancer immunology, inadvertently overshadowing the humoral arm of adaptive immunity. However, mounting evidence now demands a recalibration of this view, particularly in breast cancer, where tumor-infiltrating B cells (TIL-Bs), including terminally differentiated plasma cells, and the antibodies they produce emerge as active architects of the tumor microenvironment rather than passive bystanders. In this Review, we synthesize current insights into B-cell biology across the breast cancer ecosystem, from developmental ontogeny to functional specialization within tertiary lymphoid structures (TLSs). We dissect the dualistic nature of TIL-Bs: on one hand, clonally expanded, class-switched plasma cells and TLS-associated germinal center reactions drive potent anti-tumor immunity through antibody-dependent cytotoxicity, antigen presentation, and T-cell collaboration; on the other hand, regulatory B cells, atypical memory subsets, and pathogenic antibody isotypes foster immunosuppression, angiogenesis, and metastatic dissemination. We further examine the prognostic and predictive value of B-cell metrics across molecular subtypes, highlighting their association with response to neoadjuvant chemotherapy, anti-HER2 therapy, and immune checkpoint inhibition, especially in triple-negative and HER2-positive disease. Finally, we discuss emerging therapeutic strategies to harness anti-tumor B-cell responses while addressing the significant challenges of functional stratification, biomarker standardization, and the translation of preclinical insights into clinical benefit. Integrating B-cell function, rather than mere quantity, into next-generation pathological reporting and adaptive trial designs represents an essential frontier for precision oncology in breast cancer.