Radiation‑Induced Microglial Turnover Elicits a cGAS‑Mediated Interferon Response

Cranial radiotherapy is associated with progressive neurocognitive decline in cancer survivors, yet the mechanisms governing delayed neuroinflammatory responses remain insufficiently defined. Through integrated transcriptomic, computational, proteomic, and histological analyses, we identify a distinct microglial response emerging two weeks after irradiation, characterized by pronounced activation of interferon (IFN) signaling. Irradiation induces microglial loss, followed by compensatory proliferation, including cells harboring irradiation‑induced DNA damage, which in turn activates the cGAS–STING pathway. In silico and in vivo perturbation of pathway components establishes cGAS as the principal regulator of this response. Notably, pharmacological suppression of cGAS—but not STING or TBK1—using antisense oligonucleotides selectively attenuates the IFN program. These findings delineate a previously unrecognized, cGAS‑dependent IFN response arising during a subacute phase after cranial irradiation, providing mechanistic insight into how microglial turnover and innate immune activation may contribute to neurocognitive impairment in cancer survivors.