Biology of Brain Metastases.

Brain metastases affect up to 40% of patients with cancer and represent a major clinical challenge. Despite advances in surgery, radiotherapy, and systemic therapies, outcomes remain modest, partly due to the blood-brain barrier and the limited penetration of systemic therapies. Brain metastasis formation involves a complex sequence of events, including hematogenous spread, blood-brain barrier transmigration, and adaptation to neural niches. Recent multi-omics studies have revealed that brain metastases undergo substantial genomic, epigenetic, and transcriptomic divergence from primary and extracranial tumors. These changes promote immune evasion, metabolic reprogramming, and resistance to therapy. Tumor-glia interactions and vascular co-option further sustain metastatic progression. As conventional molecular profiling often fails to capture central nervous system-specific alterations, site-specific biopsies and liquid biopsies are gaining importance. This review provides a comprehensive overview of the molecular and cellular mechanisms underlying brain metastases and outlines emerging avenues for targeted interventions.