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Updated: Oct 4, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Ferroptosis, as the most enriched programmed cell death process in glioma, induces immunosuppression and
Tianqi Liu1, Chen Zhu1, Xin Chen1
1Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, Liaoning, China.
Background:
Immunosuppressive microenvironment is a major cause of immunotherapeutic resistance in glioma. In addition to secreting compounds, tumor cells under programmed cell death (PCD) processes release abundant mediators to modify the neighboring microenvironment. However, the complex relationship among PCD status, immunosuppressive microenvironment, and immunotherapy is still poorly understood.
Methods:
Four independent glioma cohorts comprising 1,750 patients were enrolled for analysis. The relationships among PCD status, microenvironment cellular components, and biological phenotypes were fully explored. Tissues from our hospital and experiments in vitro and in vivo were used to confirm the role of ferroptosis in glioma.
Results:
Analyses to determine enriched PCD processes showed that ferroptosis was the main type of PCD in glioma. Enriched ferroptosis correlated with progressive malignancy, poor outcomes, and aggravated immunosuppression in glioblastoma (GBM) patients. Enhanced ferroptosis was shown to induce activation and infiltration of immune cells but attenuated antitumor cytotoxic killing. Tumor-associated macrophages (TAMs) were found to participate in ferroptosis-mediated immunosuppression. Preclinically, ferroptosis inhibition combined with Programmed Cell Death 1 (PD-1) and Programmed Cell Death Ligand-1 (PD-L1) blockade generated a synergistic therapeutic outcome in GBM murine models.
Conclusions:
This work provides a molecular, clinical, and biological landscape of ferroptosis, suggesting a role of ferroptosis in glioma malignancy and a novel synergic immunotherapeutic strategy that combines immune checkpoint blockade treatment with ferroptosis inhibition.
Insights
Ferroptosis, a form of programmed cell death, drives immunosuppression in glioma, hindering immunotherapy. Inhibiting ferroptosis alongside immune checkpoint blockade offers a promising synergistic strategy for glioblastoma treatment.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Biology
Background:
- The tumor microenvironment in glioma significantly contributes to resistance against immunotherapy.
- Programmed cell death (PCD) processes in tumor cells release mediators that alter the microenvironment, but their interplay with immunosuppression and immunotherapy remains unclear.
Purpose of the Study:
- To investigate the role of different PCD types in glioma, focusing on their impact on the immunosuppressive microenvironment and therapeutic resistance.
- To explore ferroptosis as a key PCD pathway in glioma and its potential as a therapeutic target.
Main Methods:
- Analysis of four independent glioma cohorts (1,750 patients) to correlate PCD status with microenvironment, clinical outcomes, and biological phenotypes.
- In vitro and in vivo experiments, including studies with murine glioblastoma models, to validate the role of ferroptosis.
Main Results:
- Ferroptosis was identified as the predominant PCD type in glioma, associated with increased malignancy, poorer prognosis, and heightened immunosuppression in glioblastoma (GBM).
- While enhanced ferroptosis promoted immune cell activation and infiltration, it paradoxically reduced cytotoxic anti-tumor activity, with tumor-associated macrophages (TAMs) implicated in ferroptosis-mediated immunosuppression.
- Combination therapy of ferroptosis inhibition with PD-1/PD-L1 blockade demonstrated synergistic therapeutic effects in GBM models.
Conclusions:
- Ferroptosis plays a significant role in glioma progression and immune evasion.
- Targeting ferroptosis in conjunction with immune checkpoint inhibitors presents a novel and effective immunotherapeutic strategy for glioblastoma.
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