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The redox paradox in HGGs: ROS as drivers and destroyers

Pooja Kumari1, Zacary P Germon1, Evangeline R Jackson1

  • 1Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, New Lambton Heights, Newcastle, New South Wales, Australia; Precision Medicine and Health Program, Hunter Medical Research Institute, New Lambton Heights, Newcastle, New South Wales, Australia; Pediatric Stream, Mark Hughes Foundation Centre for Brain Cancer Research, College of Health, Medicine and Wellbeing, Callaghan, New South Wales, Australia.

Trends in Cancer
|March 11, 2026
PubMed

Insights

Reactive oxygen species (ROS) drive high-grade glioma growth and resistance. Targeting ROS reveals a paradox: they fuel tumors but also create vulnerabilities for new cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Reactive oxygen species (ROS) are crucial signaling molecules but their dysregulation fuels cancer progression and treatment resistance.
  • High-grade gliomas, including glioblastoma, diffuse hemispheric glioma, and diffuse midline glioma (DMG), exhibit chronic ROS production due to genetic, epigenetic, and metabolic alterations.
  • This sustained oxidative stress contributes to DNA damage, epigenetic changes, tumor proliferation, and immune evasion.

Purpose of the Study:

  • To explore the dual role of ROS in high-grade gliomas, focusing on their contribution to tumor growth and therapeutic resistance.
  • To investigate the specific mechanisms by which ROS impact DMG, including DNA/histone methylation and key signaling pathways.
  • To identify therapeutic vulnerabilities arising from the paradoxical nature of ROS in cancer.

Main Methods:

  • Review and synthesis of existing literature on ROS, oxidative stress, and high-grade gliomas.
  • Analysis of genetic, epigenetic, and metabolic alterations contributing to ROS production in gliomas.
  • Examination of ROS-dependent signaling pathways (MAPK, PI3K/Akt/mTOR) and their role in tumor survival.
  • Evaluation of emerging therapeutic strategies targeting ROS, such as NADPH oxidase inhibition and metabolic modulation.

Main Results:

  • Chronic ROS production and redox imbalance are hallmarks of high-grade gliomas, promoting tumor growth and resistance.
  • In DMG, oxidative stress exacerbates global DNA and histone hypomethylation, while activating pro-survival pathways.
  • Excess ROS paradoxically create an intrinsic vulnerability by overwhelming cellular defenses and inducing cytotoxicity.
  • Targeting ROS through novel strategies like NADPH oxidase inhibition and metabolic therapies presents potential treatment avenues.

Conclusions:

  • Understanding the complex redox paradox in high-grade gliomas is essential for developing effective therapeutic strategies.
  • Exploiting the ROS-induced vulnerabilities offers a promising approach to improve outcomes for patients with these aggressive brain tumors.
  • Further research into ROS-modulating therapies is critical for overcoming treatment resistance and enhancing patient survival in high-grade gliomas.
Keywords:
diffuse midline gliomaepigeneticsglioblastomaoncogenic signalingoxidative stressreactive oxygen species

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