Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma

Weiwei Dai, Ruotong Tian, Liubing Yu, Shasha Bian, Yuling Chen, Bowen Yin, Yuxuan Luan, Siqi Chen, Zhuoyang Fan, Rucheng Yan, Xin Pan, Yingyong Hou, Rong Li, Juxiang Chen*, Minfeng Shu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Oncolytic virotherapy holds promise for cancer treatment, but the factors determining its oncolytic activity remain unclear. Neutrophil extracellular traps (NETs) are associated with cancer progression, yet their formation mechanism and role in oncolytic virotherapy remain elusive. In this study, we demonstrate that, in glioma, upregulation of IGF2BP3 enhances the expression of E3 ubiquitin protein ligase MIB1, promoting FTO degradation via the ubiquitin-proteasome pathway. This results in increased m6A-mediated CSF3 release and NET formation. Oncolytic herpes simplex virus (oHSV) stimulates IGF2BP3-induced NET formation in malignant glioma. In glioma models in female mice, a BET inhibitor enhances the oncolytic activity of oHSV by impeding IGF2BP3-induced NETosis, reinforcing virus replication through BRD4 recruitment with the CDK9/RPB-1 complex to HSV gene promoters. Our findings unveil the regulation of m6A-mediated NET formation, highlight oncolytic virus-induced NETosis as a critical checkpoint hindering oncolytic potential, and propose targeting NETosis as a strategy to overcome resistance in oncolytic virotherapy.

Original languageEnglish
Article number131
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - Dec 2024
Externally publishedYes

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