异柠檬酸脱氢酶（IDH）状态决定了单纯疱疹病毒（oHSV）介导的代谢重编程，影响抗肿瘤免疫。

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

作者信息

Sahu Upasana, Mullarkey Matthew P, Murphy Sara A, Anderson Joshua C, Putluri Vasanta, Kamal Abu Hena Mostafa, Park Jun Hyoung, Lee Tae Jin, Ling Alexander L, Kaipparettu Benny A, Sharma Ashok, Putluri Nagireddy, Wenzel Pamela L, Willey Christopher D, Chiocca E Antonio, Markert James M, Kaur Balveen

机构信息

Department of Pathology, Medical College of Georgia at Augusta University, Augusta, GA, USA.

Georgia Cancer Center at Augusta University, Augusta, GA, USA.

出版信息

Nat Commun. 2025 Apr 24;16(1):3874. doi: 10.1038/s41467-025-58911-2.

DOI:10.1038/s41467-025-58911-2

PMID:40274791

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12022073/

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.

摘要

异柠檬酸脱氢酶（IDH）突变的鉴定揭示了代谢在胶质瘤发生中的关键作用。溶瘤性疱疹病毒（oHSV）通过肿瘤溶解启动直接肿瘤减积并激活抗肿瘤免疫，然而，关于胶质瘤代谢在决定oHSV疗效中的作用知之甚少。在此，我们发现oHSV重塑中心碳代谢，在IDH野生型胶质瘤中增加葡萄糖利用以促进氧化磷酸化，并将谷氨酰胺导向还原羧化。代谢的转变导致脂质合成增加和细胞活性氧增加。蛋白激酶C（PKC）在oHSV处理的细胞中诱导长链脂酰辅酶A合成酶4（ACSL4），导致脂质过氧化和铁死亡。铁死亡对于启动抗肿瘤免疫反应至关重要，而这对病毒疗效很重要。突变型IDH（IDHR132H）胶质瘤无法进行还原羧化，因此无法发生铁死亡。对IDHR132H的药理学阻断可诱导铁死亡和抗肿瘤免疫。本研究为使用IDHR132H抑制剂治疗接受oHSV治疗的高级别IDH突变型胶质瘤患者提供了理论依据。