The blood–brain barrier & brain metastasis

The BBB is endothelium with continuous tight junctions (claudin-5, occludin), pericyte coverage, astrocyte end-feet, and ABC efflux transporters (P-gp/ABCB1, BCRP/ABCG2) that limit drug entry; large molecules such as antibodies achieve ~0.1% of plasma levels. Metastasising cells arrest in capillary branch points, extravasate over days using cathepsin S, COX-2, HBEGF, ST6GALNAC5, and survive by hugging vessels (vascular co-option via L1CAM and β1 integrin). Reactive astrocytes first attack (plasminogen activator → FasL), which tumour cells block with serpins (neuroserpin); then astrocytes are co-opted through connexin-43 gap junctions that transfer cGAMP, activating astrocytic STING and IFN-α/TNF that support tumour growth; glioma-like neuron-tumour synapses add to it. The blood-tumour barrier in established metastases is leakier but heterogeneous, so drug levels vary lesion to lesion. Brain-penetrant small molecules (osimertinib, lorlatinib, alectinib, tucatinib, capivasertib partially, temozolomide, lomustine) changed outcomes; T-DXd shows intracranial activity despite size; focused ultrasound, intrathecal delivery and LITT are engineering solutions. Meningeal disease and leptomeningeal spread remain the hardest compartment.