Antibody-drug conjugates in breast cancer brain and leptomeningeal metastases: mechanistic insights and therapeutic progress.

Antibody-drug conjugates (ADCs) are targeted therapies that employ monoclonal antibodies to deliver potent cytotoxic agents to cancer cells. The treatment of breast cancer with brain and leptomeningeal metastases has long been limited by the assumption that the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) restrict the penetration of large molecules into the central nervous system (CNS). However, recent evidence from several trails (DESTINY-Breast12, DEBBRAH, TUXEDO-3, etc.) challenges this paradigm. In these studies, trastuzumab deruxtecan, a HER2-targeted ADC, demonstrated notable intracranial responses in patients with active CNS disease, suggesting that CNS barriers are dynamically remodeled within the tumor microenvironment to permit drug access. These findings have renewed interest in understanding how macromolecular ADCs penetrate the CNS and exert anti-tumor effects. By integrating emerging clinical evidence with key pharmacological determinants and tumor-associated microenvironmental changes, this review delineates the mechanisms governing ADC activity in brain metastases and identifies critical factors underlying intracranial response. Collectively, these insights provide a mechanistic framework to guide the rational design of next-generation ADCs and optimize therapeutic strategies for patients with advanced CNS involvement.