Senescent cell clearance suppresses post-radiotherapy glioblastoma recurrence via the IL-6/JAK2/STAT3 pathway.

Glioblastoma (GBM), the most aggressive primary brain tumor in adults, invariably recurs post-radiotherapy despite being a standard treatment. Tumor relapse within irradiated regions is characterized by heightened therapeutic resistance, which we mechanistically link to radiotherapy-induced remodeling of the tumor microenvironment. Here, we demonstrate that ionizing radiation triggers profound senescence in astrocytes, evidenced by β-galactosidase activity, G1 cell cycle arrest, p21 upregulation, and Lamin B1 downregulation. Persistent senescence signatures were observed in GFAP⁺ cells of irradiated mouse brains for ≥ 49 days. Conditioned medium from senescent astrocytes markedly enhanced proliferation, migration, and invasion of GBM cells. Intracranial U251 xenografts in pre-irradiated mice exhibited accelerated tumor growth and reduced survival, phenotypes rescued by the senolytic agent ABT-263. Transcriptomic profiling identified IL6 as the predominant senescence-associated secretory phenotype (SASP) factor elevated in irradiated astrocytes. Senescent conditioned medium activated JAK2/STAT3 signaling in GBM cells, effects abrogated by ABT-263 or tocilizumab (IL6R neutralizing antibody). Functional assays confirmed that IL6 blockade suppressed GBM aggressiveness, mirroring senolytic treatment outcomes. Our findings establish radiation-induced astrocyte senescence as a critical driver of GBM recurrence through IL6-mediated JAK2/STAT3 activation, nominating senolytics as promising adjuvants to improve radiotherapy efficacy.