A spatiotemporal atlas of radiation-induced brain injury reveals dysfunction of the blood-CSF barrier

Radiotherapy for brain tumors frequently induces irreversible cognitive decline, yet the underlying mechanisms remain poorly understood. Here, we present an integrated single-cell and spatial transcriptomic atlas of radiation-induced brain injury (RIBI) in mice, spanning the acute to chronic phases. We reveal that the early-delayed phase following irradiation represents a critical window during which the blood-cerebrospinal fluid barrier (BCSFB) integrity is compromised. This disruption results from the selective depletion of a radiosensitive Tmsb4x + epithelial subpopulation in the choroid plexus, which functions as a gatekeeper for the BCSFB. Consequently, CSF-derived macrophages excessively infiltrate the periventricular niche and engage in spatial crosstalk with interferon-responsive microglia. This dysregulated immune axis sustains chronic neuroinflammation, driving the late-stage neurodegeneration and cognitive impairment. In conclusion, our study establishes a high-resolution spatiotemporal framework and positions the BCSFB as a pivotal immune gateway and a promising therapeutic target for mitigating RIBI.