Aging‐Driven Blood–Brain Barrier Dysfunction and Its Impact on CNS Cancer Susceptibility: A Comprehensive Narrative Review

ABSTRACT Background Aging significantly affects the structural and functional integrity of the blood–brain barrier (BBB), increasing the susceptibility of the central nervous system (CNS) to both primary and metastatic cancers. As the BBB deteriorates, it promotes tumor cell infiltration, alters drug permeability, and contributes to a proinflammatory microenvironment that supports tumor progression. These age‐related changes present major obstacles in the effective treatment of CNS malignancies in elderly patients. Methods This review synthesizes current literature on the mechanisms of BBB aging and its impact on CNS cancer development and treatment. It examines key structural alterations, such as tight junction protein loss, endothelial dysfunction, and pericyte reduction, as well as functional changes including impaired immune regulation and transporter dysfunction. The review also evaluates therapeutic challenges and emerging strategies to overcome the BBB barrier in the aging brain. Results Aging induces BBB dysfunction by weakening cellular junctions, disrupting the neurovascular unit, and promoting chronic neuroinflammation. These alterations facilitate tumor cell entry and survival in the brain and reduce the effectiveness of cancer therapies due to impaired drug delivery. Promising interventions, including nanoparticle‐based therapies, focused ultrasound techniques, and targeted chemoimmunotherapy, are under development to enhance therapeutic outcomes in elderly patients. Conclusion The age‐related breakdown of the BBB contributes significantly to increased cancer risk and therapeutic resistance in the CNS. Addressing BBB dysfunction through age‐specific interventions and advanced drug delivery strategies is critical to improving outcomes for older adults with CNS malignancies. Further research into the molecular pathways of BBB aging will support the development of personalized and effective treatments.