Decoding the mechanisms underlying breast cancer brain metastasis: paving the way for precision therapeutics

The development of brain metastasis is a major cause of significantly reduced survival in breast cancer patients. The initiation and progression of breast cancer brain metastasis (BCBM) involve multiple distinct molecular pathways and reprogramming of the tumor microenvironment (TME). This review systematically summarizes key mechanisms underlying BCBM, including epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and the spatiotemporal dynamics of metabolic reprogramming regulated by critical signaling pathways during brain colonization. In particular, we highlight emerging mechanisms of breaching the specialized brain multifunctional barriers. Furthermore, this review provides an in-depth analysis of the cooperative immune-suppressive network within the BCBM TME, emphasizing the crosstalk among various immune cell components (such as T cells, B cells, macrophages, neutrophils, NK cells, MDSCs) and intracranial-specific cellular elements (including astrocytes, microglia, brain metastasis-associated fibroblasts). Through the complex interplay, these cells collectively facilitate immune evasion and metastatic outgrowth. Accordingly, we discuss the current clinical management of BCBM and potential future directions. Deeper mechanistic insights are expected to offer novel biomarkers and reveal new targets for developing precision therapeutic strategies against BCBM.