Translational barriers and emerging strategies for bispecific antibody therapy in breast cancer

Breast cancer (BC) remains a highly heterogeneous malignancy, with human epidermal growth factor receptor 2 (HER2)-positive BC and triple-negative breast cancer (TNBC) subtypes representing particularly formidable clinical challenges. Bispecific antibodies (BsAbs), which engage two distinct tumor-associated antigens (TAAs), have emerged as a powerful modality in cancer immunotherapy by reshaping antitumor immune microenvironments. This review provides a systematic overview of the principal BsAbs structural formats and delineates their six core mechanisms of action. We critically synthesize data from representative global clinical trials to evaluate the current landscape of BsAbs candidates. Furthermore, we dissect four key translational hurdles, present a comparative analysis of the distinct barriers encountered in solid breast tumors versus hematological malignancies, and propose a three-term developmental framework that integrates combinatorial strategies, manufacturing advancements, and emerging technologies. Collectively, this review offers subtype-specific optimization guidelines, with the goal of informing the rational design, preclinical development, and eventual clinical translation of BsAb-based therapies for BC.