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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.
Nature Communications
|April 24, 2025
Summary
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.
