Year: 2025
Type: article
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.
Source: Nature Communications
Authors: 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 Sharma, Nagireddy Putluri, Pamela L. Wenzel, Christopher D. Willey, E. Antonio Chiocca, James M. Markert, Balveen Kaur
Institutions: Augusta University, The University of Texas Health Science Center at Houston, The University of Texas MD Anderson Cancer Center, University of Alabama at Birmingham, UAB Medicine, Baylor College of Medicine, Dan L Duncan Comprehensive Cancer Center, Brigham and Women's Hospital, Augusta University Health
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, Cancer Prevention and Research Institute of Texas, Emory University, Dan L. Duncan Cancer Center, Baylor College of Medicine, Augusta University, National Institutes of Health, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: G1160372751, G2127060285, G2681005513, G3295383696, G418187648, Proteomics and Metabolomics Core Facility, Optimizing oncolytic virus therapy for glioblastoma, G5465708471, G5508324684, G5524839908, G5749691131, G6680608540, G6814760807, Decoding tumor metabolic and immunologic interactions driving racial disparity in African American patients with bladder cancer., G7557813972, G7579377447, G7837447426, G9000240210, G9000246192, G9000312272, Next Gen Virotherapy for GBM, Next generation oncolytic virotherapy targeting AKT and ERK signaling in glioma, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, Circumventing Barriers to Effective Oncolytic Virotherapy of Malignant Gliomas
OpenAlex ID: W4409765321