T-cell homing and delivery strategies: Under physiological conditions, circulating T-cells migrate into CSF through vessels located within the meninges and the choroid plexus, directed by cytokine signals and facilitated by endothelial adhesion molecules.^119,120 Subsequently, migration from the perivascular (CSF-filled) space through the glia limitans depends on T-cell reactivation. While IV-delivered T-cells may be trapped in the lungs or blocked by the BBB, preclinical studies suggest that T-cells can enter the CNS after residing transiently in the lung and associated lymphoid tissues.¹²¹ IV-infused T-cells can then follow similar migration routes into the CSF as T-cells under immune surveillance. To overcome natural anatomical barriers of the CNS, recent clinical trials have explored various delivery routes for CAR T-cells, including IV,²² ICV, and IT delivery⁹⁵ ICV administration, typically performed via an Ommaya reservoir, may encounter an anti-inflammatory immune environment with low adhesion molecule expression, hindering attachment to the pia mater, glia limitans, or choroid plexus epithelium. Therefore, not all of the ICV-injected T-cells may be able to migrate from the CSF into the CNS parenchyma. On the other side, cells that have successfully migrated into the CNS may persist within the CNS parenchyma or adjacent structures. IT delivery faces challenges in glioblastoma due to the tumor’s highly immunosuppressive and hypoxic environment, leading to T-cell exhaustion.²¹ Innovative approaches like low-intensity pulsed focused ultrasound with microbubble application (LIPU/MB) can enhance IV delivery by temporarily opening the blood–brain barrier (BBB), aiding drug¹²² and cell penetration into the CNS.¹²³