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GDF15 Drives Glioblastoma Radioresistance by Inhibiting Ferroptosis and Remodeling the Immune Microenvironment
Wenqing Feng1, Yantan Liu1, Qinghua Zhang1
1Department of Radiation Oncology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, Guangdong, China.
International Journal of Biological Sciences
|November 24, 2025
Summary
Growth differentiation factor 15 (GDF15) promotes glioblastoma radioresistance by preventing ferroptosis and creating an immunosuppressive environment. Targeting GDF15 may improve radiotherapy effectiveness for recurrent glioblastoma.
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Radiotherapy is a cornerstone treatment for glioblastoma (GBM), but treatment failure due to radioresistance and subsequent tumor recurrence remains a significant clinical challenge.
- Previous research indicated elevated levels of Growth Differentiation Factor 15 (GDF15) in radioresistant GBM cells and recurrent GBM tissues, suggesting a potential role in treatment resistance.
- The precise mechanisms by which GDF15 contributes to glioblastoma radioresistance were not fully understood.
Purpose of the Study:
- To elucidate the role of GDF15 in glioblastoma radioresistance.
- To investigate the molecular mechanisms underlying GDF15-mediated radioresistance, including its effects on ferroptosis and the tumor immune microenvironment.
- To assess the potential of GDF15 as a therapeutic target for overcoming radioresistance in glioblastoma.
Main Methods:
- Analysis of GDF15 expression in radioresistant GBM cells and patient tissues.
- Experimental manipulation of GDF15 levels in GBM models to assess its impact on radiosensitivity.
- Investigation of GDF15's effect on radiation-induced ferroptosis, including assessment of NRF2 protein stability and ubiquitin-mediated degradation.
- Evaluation of GDF15's influence on macrophage polarization and infiltration into the tumor microenvironment post-radiation.
Main Results:
- GDF15 was confirmed to be highly expressed in radioresistant GBM and associated with tumor recurrence.
- GDF15 significantly promoted radioresistance in glioblastoma models.
- GDF15 was found to suppress ferroptosis by stabilizing NRF2 protein, thereby reducing its ubiquitin-mediated degradation.
- GDF15 induced M2-type macrophage infiltration, leading to an immunosuppressive tumor microenvironment that further enhanced radioresistance.
Conclusions:
- GDF15 is a critical mediator of glioblastoma radioresistance.
- GDF15 confers radioresistance by inhibiting ferroptosis and promoting an immunosuppressive microenvironment via M2 macrophage recruitment.
- GDF15 represents a promising therapeutic target to enhance the efficacy of radiotherapy for glioblastoma.
