2. Academic Validation
  3. IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity

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

  • Nat Commun. 2025 Apr 24;16(1):3874. doi: 10.1038/s41467-025-58911-2.
Upasana Sahu 1 2,  Matthew P Mullarkey 3,  Sara A Murphy 4 5 6,  Joshua C Anderson 7,  Vasanta Putluri 8,  Abu Hena Mostafa Kamal 8 9,  Jun Hyoung Park 10,  Tae Jin Lee 11,  Alexander L Ling 12,  Benny A Kaipparettu 10,  Ashok Sharma 11,  Nagireddy Putluri 8 9,  Pamela L Wenzel 13,  Christopher D Willey 7,  E Antonio Chiocca 12,  James M Markert 14,  Balveen Kaur 15 16
Affiliations

Affiliations

  • 1 Department of Pathology, Medical College of Georgia at Augusta University, Augusta, GA, USA. usahu@augusta.edu.
  • 2 Georgia Cancer Center at Augusta University, Augusta, GA, USA. usahu@augusta.edu.
  • 3 Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 4 Department of Pathology, Medical College of Georgia at Augusta University, Augusta, GA, USA.
  • 5 Georgia Cancer Center at Augusta University, Augusta, GA, USA.
  • 6 University of Texas MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
  • 7 Department of Radiation Oncology, Marnix E. Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 8 Advanced Technology Cores, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 9 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 10 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 11 Center for Biotechnology and Genomic Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA.
  • 12 Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.
  • 13 Department of Integrative Biology & Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 14 Department of Neurosurgery, Marnix E. Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
  • 15 Department of Pathology, Medical College of Georgia at Augusta University, Augusta, GA, USA. bkaur@augusta.edu.
  • 16 Georgia Cancer Center at Augusta University, Augusta, GA, USA. bkaur@augusta.edu.
PMID: 40274791 DOI: 10.1038/s41467-025-58911-2
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.

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