Bridging the gap: unlocking the potential of emerging drug therapies for brain metastasis

Brain metastasis (BrM) remains an unmet clinical need in advanced cancers with an increasing incidence and poor prognosis. The limited response to various treatments is mainly derived from the presence of the substantive barrier, blood–brain barrier (BBB) and brain–tumor barrier (BTB), which hinders the access of potentially effective therapeutics to the metastatic tumor of brain. Recently, the understanding of the structural and molecular features of the BBB/BTB has led to the development of efficient strategies to enhance BBB/BTB permeability and deliver drugs across the BBB/BTB to elicit the antitumor response against BrM. Meanwhile, novel agents capable of penetrating the BBB have rapidly developed and evaluated in pre-clinical studies and clinical trials, with both targeted therapies and immunotherapies demonstrating impressive intracranial activity against BrM. In this review, we summarize the recent advances in the biological properties of the BBB/BTB, and the emerging strategies for BBB/BTB permeabilization and drug delivery across the BBB/BTB. We also discuss the emerging targeted therapies and immunotherapies against BrM tested in clinical trials. Additionally, we provide our viewpoints on accelerating clinical translation of novel drugs into clinic for patients of BrM. Although still facing challenges, we expect this review to benefit the future development of novel therapeutics specifically from clinical perspective.