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IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity

Author

Listed:
  • Upasana Sahu

    (Medical College of Georgia at Augusta University
    Georgia Cancer Center at Augusta University)

  • Matthew P. Mullarkey

    (The University of Texas Health Science Center at Houston)

  • Sara A. Murphy

    (Medical College of Georgia at Augusta University
    Georgia Cancer Center at Augusta University
    University of Texas MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences)

  • Joshua C. Anderson

    (University of Alabama at Birmingham)

  • Vasanta Putluri

    (Baylor College of Medicine)

  • Abu Hena Mostafa Kamal

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Jun Hyoung Park

    (Baylor College of Medicine)

  • Tae Jin Lee

    (Medical College of Georgia at Augusta University)

  • Alexander L. Ling

    (Brigham and Women’s Hospital)

  • Benny A. Kaipparettu

    (Baylor College of Medicine)

  • Ashok Sharma

    (Medical College of Georgia at Augusta University)

  • Nagireddy Putluri

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Pamela L. Wenzel

    (The University of Texas Health Science Center at Houston)

  • Christopher D. Willey

    (University of Alabama at Birmingham)

  • E. Antonio Chiocca

    (Brigham and Women’s Hospital)

  • James M. Markert

    (The University of Alabama at Birmingham)

  • Balveen Kaur

    (Medical College of Georgia at Augusta University
    Georgia Cancer Center at Augusta University)

Abstract

Identification of isocitrate dehydrogenase (IDH) mutations has uncovered the crucial role of metabolism in gliomagenesis. Oncolytic herpes virus (oHSV) initiates direct tumor debulking by tumor lysis and activates anti-tumor immunity, however, little is known about the role of glioma metabolism in determining oHSV efficacy. Here we identify that oHSV rewires central carbon metabolism increasing glucose utilization towards oxidative phosphorylation and shuttling glutamine towards reductive carboxylation in IDH wildtype glioma. The switch in metabolism results in increased lipid synthesis and cellular ROS. PKC induces ACSL4 in oHSV treated cells leading to lipid peroxidation and ferroptosis. Ferroptosis is critical to launch an anti-tumor immune response which is important for viral efficacy. Mutant IDH (IDHR132H) gliomas are incapable of reductive carboxylation and hence ferroptosis. Pharmacological blockade of IDHR132H induces ferroptosis and anti-tumor immunity. This study provides a rationale to use an IDHR132H inhibitor to treat high grade IDH-mutant glioma patients undergoing oHSV treatment.

Suggested Citation

  • Upasana Sahu & Matthew P. Mullarkey & Sara A. Murphy & Joshua C. Anderson & Vasanta Putluri & Abu Hena Mostafa Kamal & Jun Hyoung Park & Tae Jin Lee & Alexander L. Ling & Benny A. Kaipparettu & Ashok , 2025. "IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58911-2
    DOI: 10.1038/s41467-025-58911-2
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    References listed on IDEAS

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