Khoi Nguyen

Background: Glioblastoma (GBM) is one of the most lethal primary brain tumors, with nearly universal recurrence despite aggressive multimodal treatment. A key driver of treatment failure is the presence of glioblastoma stem-like cells (GSCs), which possess enhanced survival mechanisms enabling tolerance of radiation-induced DNA damage.¹ These cells exhibit constitutive replication stress, slower replication fork progression, and persistent activation of DNA damage response (DDR) signaling, facilitating efficient repair of radiation-induced injury.¹ Transcriptional analyses of irradiated GSCs identified Growth Differentiation Factor 15 (GDF15) as a radiation-induced factor centrally involved in tumor survival and recurrence.² Despite this, the mechanistic role of GDF15 in coordinating radioresistance across intracellular and immunological domains has not been fully characterized.

Objective: This narrative literature review investigates the hypothesis that radiation-induced GDF15 serves as a central mechanistic mediator of glioblastoma radioresistance by suppressing ferroptosis, remodeling the tumor immune microenvironment, and correlating with poor clinical outcomes, thereby representing a rational therapeutic target to enhance radiation sensitivity.

Search Methods: A systematic literature search was conducted using PubMed and Google Scholar from 2018 to 2025. MeSH terms and keywords included: “glioblastoma,” “GDF15,” “radioresistance,” “glioblastoma stem cells,” “ferroptosis,” “tumor microenvironment,” “replication stress,” “NRF2,” “TAZ/WWTR1,” “macrophage polarization,” “CRISPR,” and “immunotherapy.” Studies reporting mechanistic, translational, or clinical findings relevant to GDF15 in glioblastoma or glioma were included.

Results: Carruthers et al. demonstrated that CD133⁺ GSCs exhibit constitutive replication stress and DDR activation, enabling efficient radiation-induced DNA repair and contributing to radioresistance.¹ Bentaberry-Rosa et al. showed that ionizing radiation significantly upregulates GDF15 expression in GSCs via WWTR1/TAZ signaling, and that GDF15 knockdown reduces neurosphere formation and sensitizes cells to radiation.² Feng et al. established that GDF15 stabilizes NRF2, preserving intracellular glutathione and limiting lipid peroxidation, thereby suppressing radiation-induced ferroptotic cell death. GDF15 also promoted M2-like macrophage polarization, fostering an immunosuppressive tumor microenvironment.³ Guo et al. analyzed public glioma datasets (TCGA and CGGA) and demonstrated that GDF15 expression increases with tumor grade and is associated with significantly reduced patient survival, supporting GDF15 as a clinically meaningful prognostic biomarker.⁴ Finally, Zou et al. employed tumor microenvironment-responsive CRISPR-Cas9 nanoparticles to selectively disrupt GDF15 in orthotopic GBM models, resulting in enhanced immune activation and improved therapeutic response when combined with anti-PD-1 immunotherapy.⁵

Conclusion: This review identifies GDF15 as a central node coordinating glioblastoma radioresistance through complementary intracellular and immunological mechanisms. Radiation-induced GDF15 suppresses ferroptotic cell death via NRF2 stabilization, promotes immunosuppressive macrophage polarization, and correlates with tumor aggressiveness and poor survival in clinical datasets. Preclinical targeting of GDF15 via CRISPR-Cas9 nanoparticle delivery enhanced immunotherapy efficacy, highlighting its translational potential. Future research should explore the combination of GDF15 inhibition with standard radiotherapy and immunotherapy in clinical settings to determine whether abrogating GDF15 signaling can meaningfully improve outcomes for glioblastoma patients.

Works Cited

1.  Carruthers RD, Ahmed SU, Ramachandran S, et al. Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-Like Cells. Cancer Res. 2018;78(17):5060-5071. doi:10.1158/0008-5472.CAN-18-0569
2. Bentaberry-Rosa A, Nicaise Y, Delmas C, et al. Overexpression of Growth Differentiation Factor 15 in Glioblastoma Stem Cells Promotes Their Radioresistance. Cancers (Basel). 2023;16(1):27. doi:10.3390/cancers16010027
3. Feng W, Liu Y, Zhang Q, et al. GDF15 Drives Glioblastoma Radioresistance by Inhibiting Ferroptosis and Remodeling the Immune Microenvironment. Int J Biol Sci. 2025;21(15):6794-6807. doi:10.7150/ijbs.115721
4. Guo L, Chen Y, Hu S, et al. GDF15 Expression in Glioma Is Associated With Malignant Progression, Immune Microenvironment, and Serves as a Prognostic Factor. CNS Neurosci Ther. 2022;28(1):158-171.
5. Zou C, Liu X, Wang W, et al. Targeting GDF15 to Enhance Immunotherapy Efficacy in Glioblastoma Through Tumor Microenvironment-Responsive CRISPR-Cas9 Nanoparticles. J Nanobiotechnol. 2025;23(1):126. doi:10.1186/s12951-025-03182-8