Deciphering the Blood-Brain Barrier Paradox in Brain Metastasis Development and Therapy

Gatekeeper or accomplice? That is the paradoxical role of the blood-brain barrier (BBB) in developing brain metastasis (BM). BM occurs when cancerous cells from primary cancer elsewhere in the body gain the ability to metastasize and invade the brain parenchyma despite the formidable defense of the BBB. These metastatic cells manipulate the BBB's components, changing them from gatekeepers of the brain to accomplices that aid in their progression into the brain tissue. This dual role of the BBB-as both a protective system and a potential facilitator of metastatic cells-highlights its complexity. Even with metastasis therapy such as chemotherapy, BM usually recurs due to the BBB limiting the crossing of drugs via the efflux transporters; therefore, treatment efficacy is limited. The pathophysiology is also complex, and our understanding of the paradoxical interplay between the BBB components and metastatic cells still needs to be improved. However, advancements in clinical research are helping to bridge the knowledge gap, which is essential for developing effective metastasis therapy. By targeting the BBB neurovascular unit components such as the polarization of microglia, astrocytes, and pericytes, or by utilizing technological tools like focused ultrasound to transiently disrupt the BBB and therapeutic nanoparticles to improve drug delivery efficiency to BM tissue, we can better address this pathology. This narrative review delves into the latest literature to analyze the paradoxical role of the BBB components in the manifestation of BM and explores potential therapeutic avenues targeting the BBB-tumor cell interaction.