A Tri-Phasic View of the Microenvironment in Breast Cancer Brain Metastasis

Abstract

Breast cancer brain metastasis (BCBM) is driven by microenvironmental remodeling across three interconnected phases: the primary tumor microenvironment (TME) licenses dissemination, the pre-metastatic niche (PMN) primes the brain, and the established metastatic niche sustains outgrowth through central nervous system (CNS)-resident cell interactions. These phases are individually established; we integrate them through cross-phase signaling axes, exemplified by the proposed IL-6$\rightarrow$extracellular vesicle (EV)$\rightarrow$blood-brain barrier (BBB) disruption cascade, that link tumor-associated macrophage-driven epithelial-mesenchymal transition to PMN conditioning and niche maintenance. We integrate single-cell and spatial transcriptomic insights, discuss brain-specific mechanisms including astrocytic STAT3/connexin 43 signaling, neuronal contributions, and the neurovascular unit, and evaluate emerging therapies with emphasis on antibody-drug conjugates with intracranial activity. Subtype-specific differences between HER2-positive and triple-negative breast cancer brain metastases and key translational barriers are systematically addressed.