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Ferroptosis in glioblastoma: Molecular determinants, immune crosstalk, and therapeutic opportunities
Jihu Wang1, Guifeng Zhang2, Zhiming Zheng3
1Department of Neurosurgery, Jining No.1 People's Hospital, Shandong First Medical University, Jining, China.
Abstract:
Glioblastoma(GBM) is characterized by rapid recurrence and resistance to radiochemotherapy, highlighting the need for therapeutic vulnerabilities that extend beyond genetic subtypes. Ferroptosis, an iron-dependent form of lipid peroxidation-driven cell death, has emerged as a promising but complex vulnerability in GBM. In this review, we summarize how ferroptotic sensitivity is shaped by core iron-lipid-antioxidant machinery and by GBM-specific regulatory layers, including mitophagy, m6A-dependent GPX4 regulation, lipid metabolic remodeling, and DNA damage-associated stress responses. We further discuss how ferroptosis interacts with the GBM immune microenvironment, where it may either promote antitumor immunity or be exploited to induce immune-cell dysfunction. Finally, we evaluate therapeutic strategies that combine ferroptosis modulation with radiotherapy, temozolomide chemotherapy, immunotherapy, and nanomedicine-based delivery. We propose that ferroptosis-targeted strategies in GBM should be guided by tumor context, immune-cell preservation, and biomarker-based patient stratification.
Insights
Glioblastoma (GBM) exhibits ferroptosis, an iron-dependent cell death, as a complex vulnerability. Targeting ferroptosis offers new therapeutic strategies for GBM, considering tumor context and immune interactions.
Area of Science:
- Oncology
- Cell Death Mechanisms
- Cancer Biology
Background:
- Glioblastoma (GBM) is highly recurrent and resistant to standard treatments.
- Ferroptosis, a form of regulated cell death, presents a potential therapeutic vulnerability in GBM.
- Understanding GBM's unique regulatory layers influencing ferroptosis is crucial.
Purpose of the Study:
- To review the mechanisms governing ferroptosis sensitivity in GBM.
- To explore the interplay between ferroptosis and the GBM immune microenvironment.
- To evaluate therapeutic strategies targeting ferroptosis in GBM.
Main Methods:
- Literature review of ferroptosis mechanisms in Glioblastoma.
- Analysis of GBM-specific regulatory pathways impacting ferroptosis.
- Evaluation of combination therapies involving ferroptosis modulators.
Main Results:
- Ferroptosis sensitivity in GBM is modulated by iron-lipid-antioxidant systems and specific GBM layers like mitophagy and GPX4 regulation.
- Ferroptosis can influence the GBM immune microenvironment, potentially promoting anti-tumor immunity or causing immune dysfunction.
- Various therapeutic strategies combining ferroptosis induction with conventional treatments and nanomedicine show promise.
Conclusions:
- Ferroptosis represents a complex vulnerability in Glioblastoma (GBM) that can be therapeutically exploited.
- Strategies targeting ferroptosis in GBM should consider tumor context, immune preservation, and patient stratification using biomarkers.
