The curse of blood-brain barrier and blood-tumor barrier in malignant brain tumor treatment.

The blood-brain barrier (BBB) is crucial for brain homeostasis but is a major obstacle in delivering anticancer drugs to brain tumors. However, this perspective requires re-evaluation, particularly for malignant brain tumors, such as gliomas and brain metastases. In these aggressive tumors, the BBB undergoes significant alterations, leading to the formation of a more permeable blood-tumor barrier. While this increased permeability allows better drug penetration, heterogeneity in blood-tumor barrier (BTB) integrity across different tumor regions remains a challenge. Additionally, the main challenge in treating brain tumors lies not in BBB penetration but in the lack of effective drugs. Conventional chemotherapies, including temozolomide and nitrosourea agents, have shown limited efficacy, and resistance mechanisms often reduce their long-term benefits. The "BBB curse" has often been blamed for the slow progress in drug development. However, emerging evidence suggests that even larger-molecule therapies, such as antibody-drug conjugates, can successfully target brain tumors. This review aims to critically reassess the roles of the BBB and BTB in brain tumor therapy, highlighting their impact on drug delivery and evaluating the current landscape of chemotherapeutic strategies. Furthermore, it explores new approaches to overcome treatment limitations, emphasizing the need for personalized and targeted therapeutic strategies.