GDF15 Drives Glioblastoma Radioresistance by Inhibiting Ferroptosis and Remodeling the Immune Microenvironment

Radiotherapy is a primary treatment for glioblastoma (GBM), yet its effectiveness is limited by frequent recurrence due to radioresistance. Our previous studies have illustrated that GDF15 is highly expressed in radioresistant GBM cells and correlates strongly with recurrent GBM tissue. However, its role in radioresistance remained unclear. Here, we demonstrate that GDF15 promotes radioresistance by suppressing ferroptosis and altering the immune microenvironment. Mechanistically, GDF15 alleviates radiation-induced ferroptosis by stabilizing NRF2 protein through reduced ubiquitin-mediated degradation. Additionally, after radiation, GDF15 promotes M2 type macrophage infiltration, fostering an immunosuppressive microenvironment that further supports radioresistance. These findings emphasize GDF15 as a key mediator of GBM radioresistance and a potential therapeutic target to improve radiotherapy outcomes.