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.

中文翻译：

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弥合差距：释放新兴药物疗法治疗脑转移的潜力


脑转移 （BrM） 仍然是晚期癌症中未满足的临床需求，发病率不断增加，预后不良。对各种治疗的有限反应主要源于存在实质性屏障、血脑屏障 （BBB） 和脑肿瘤屏障 （BTB），这阻碍了潜在有效疗法进入脑转移性肿瘤。最近，对 BBB/BTB 的结构和分子特征的理解导致了有效策略的开发，以增强 BBB/BTB 通透性并跨 BBB/BTB 递送药物以引发针对 BrM 的抗肿瘤反应。与此同时，能够穿透 BBB 的新型药物在临床前研究和临床试验中迅速开发和评估，靶向治疗和免疫治疗都显示出令人印象深刻的针对 BrM 的颅内活性。在这篇综述中，我们总结了 BBB/BTB 生物学特性的最新进展，以及 BBB/BTB 中 BBB/BTB 透化和药物递送的新兴策略。我们还讨论了在临床试验中测试的新兴靶向疗法和针对 BrM 的免疫疗法。此外，我们还为加速 BrM 患者将新药临床转化为临床提供了我们的观点。尽管仍面临挑战，但我们预计本综述将有利于新疗法的未来发展，特别是从临床角度来看。