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Updated: May 10, 2025
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Published on: March 7, 2025
IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity
Upasana Sahu1,2, Matthew P Mullarkey3, Sara A Murphy4,5,6
1Department of Pathology, Medical College of Georgia at Augusta University, Augusta, GA, USA. usahu@augusta.edu.
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.
Insights
Oncolytic herpes virus (oHSV) alters glioma metabolism, promoting ferroptosis and anti-tumor immunity in IDH wildtype tumors. Inhibiting mutant IDH (IDHR132H) can induce ferroptosis and immunity, offering a treatment strategy for IDH-mutant gliomas.
Area of Science:
- Oncology
- Virology
- Metabolic pathways
Background:
- Metabolism is crucial in gliomagenesis, with isocitrate dehydrogenase (IDH) mutations impacting tumor development.
- Oncolytic herpes virus (oHSV) offers direct tumor debulking and activates anti-tumor immunity, but its efficacy in gliomas is influenced by tumor metabolism.
Purpose of the Study:
- To investigate the role of glioma metabolism in determining oncolytic herpes virus (oHSV) efficacy.
- To elucidate the metabolic rewiring induced by oHSV in IDH wildtype and mutant gliomas.
- To explore the potential of targeting IDH-mutant metabolism for enhanced oHSV therapy.
Main Methods:
- Analysis of central carbon metabolism shifts in IDH wildtype glioma treated with oHSV.
- Assessment of lipid synthesis, reactive oxygen species (ROS) production, and ferroptosis induction.
- Investigation of the impact of mutant IDH (IDHR132H) on reductive carboxylation and ferroptosis.
- Evaluation of pharmacological blockade of IDHR132H in inducing ferroptosis and anti-tumor immunity.
Main Results:
- oHSV increases glucose utilization towards oxidative phosphorylation and glutamine towards reductive carboxylation in IDH wildtype glioma.
- This metabolic switch leads to increased lipid synthesis, cellular ROS, and PKC-induced ACSL4, resulting in lipid peroxidation and ferroptosis.
- Ferroptosis is critical for initiating an anti-tumor immune response, enhancing viral efficacy.
- IDH-mutant (IDHR132H) gliomas cannot perform reductive carboxylation and are resistant to ferroptosis.
- Pharmacological inhibition of IDHR132H successfully induces ferroptosis and anti-tumor immunity in these gliomas.
Conclusions:
- oHSV treatment significantly rewires glioma metabolism, promoting ferroptosis and anti-tumor immunity in IDH wildtype gliomas.
- IDH-mutant gliomas exhibit metabolic resistance to oHSV-induced ferroptosis.
- Targeting IDH-mutant gliomas with IDHR132H inhibitors can restore ferroptosis and anti-tumor immunity, providing a rationale for combination therapy.
