Novel strategies to overcome the blood-brain barrier in triple-negative breast cancer brain metastases.

Abstract

Triple-negative breast cancer-the most aggressive breast cancer subtype-has a high propensity for brain metastases, with limited treatments and poor prognosis. The blood-brain barrier, long viewed as an impermeable therapeutic sanctuary, is the core barrier to effective care. This Review advocates a key paradigm shift for clinical and translational research: from merely circumventing the blood-brain barrier to actively targeting and exploiting its biology. We delineate triple-negative breast cancer-specific mechanisms of blood-brain barrier breach and evaluate emerging therapies via a clinically actionable three-pillar framework: physical and focal blood-brain barrier disruption, biological blood-brain barrier exploitation, and microenvironmental modulation. We also summarise advances in preclinical models for blood-brain barrier-targeted drug development. Synthesising the latest preclinical and clinical evidence, this Review provides a translational roadmap for unmet clinical needs, emphasising that integrated, blood-brain barrier-centric strategies are crucial to improving patient outcomes.