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IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity
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IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity
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Journal Article
IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity
2025
Overview
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.
The role of glioma cellular metabolism in response to oncolytic herpes virus (oHSV) therapy remains to be studied. Here the authors report that oHSV induces metabolic reprogramming in IDH wildtype glioma cells, leading to ferroptosis and anti-tumor immune response. Pharmacological blockade of mutant IDH enhances glioma cell sensitivity to oHSV therapy.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
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/ 14/28
/ 14/34
/ 14/63
/ 38/77
/ 38/91
/ 49/47
/ 59
/ 59/57
/ 82/29
/ 96/106
/ Animals
/ Brain Neoplasms - immunology
/ Brain Neoplasms - metabolism
/ Glioma
/ Humanities and Social Sciences
/ Humans
/ Immunity
/ Isocitrate Dehydrogenase - genetics
/ Isocitrate Dehydrogenase - metabolism
/ Lipids
/ Mice
/ Mutants
/ Mutation
/ Oncolytic Virotherapy - methods
/ Oncolytic Viruses - genetics
/ Oncolytic Viruses - immunology
/ Oncolytic Viruses - physiology
/ Reactive Oxygen Species - metabolism
/ Science
/ Tumors
