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The brain's blood vessels are sealed tight and fitted with pumps that eject most drugs. That protects the brain from poisons but also from chemotherapy and antibodies. Cancer cells that do squeeze through recruit the brain's own support cells, astrocytes, to feed and shield them.
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.
A gated city with customs officers who throw out most goods (efflux pumps). Smugglers who get in bribe the local guards (astrocytes) to feed them. Drugs that work here are either small enough to slip past customs or arrive by a special convoy (focused ultrasound, intrathecal delivery).
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