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

doi:10.1038/s41467-023-44576-2

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

Nat Commun. 2024 Jan 2;15(1):131. doi: 10.1038/s41467-023-44576-2.

Authors

Weiwei Dai^{1

2}, Ruotong Tian¹, Liubing Yu^{1

2}, Shasha Bian^{1

2}, Yuling Chen¹, Bowen Yin^{1

2}, Yuxuan Luan^{1

2}, Siqi Chen^{1

2}, Zhuoyang Fan^{1

3}, Rucheng Yan¹, Xin Pan^{4

5}, Yingyong Hou⁶, Rong Li⁷, Juxiang Chen⁸, Minfeng Shu^{9

10}

Affiliations

¹ Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
² Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
³ Department of Interventional Radiology, Zhongshan hospital, Fudan University, Shanghai, China.
⁴ School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁵ Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, China.
⁶ Department of Pathology, Zhongshan hospital, Fudan University, Shanghai, China.
⁷ Department of Neurosurgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China.
⁸ Department of Neurosurgery, Shanghai Changhai Hospital, Naval Medical University, Shanghai, China. juxiangchen@smmu.edu.cn.
⁹ Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. minfeng_shu@fudan.edu.cn.
¹⁰ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. minfeng_shu@fudan.edu.cn.

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.

MeSH terms

Animals
Drug Resistance, Neoplasm
Female
Glioma* / genetics
Mice
Nuclear Proteins
Oncolytic Virotherapy* / methods
Oncolytic Viruses* / genetics
Simplexvirus / genetics
Transcription Factors

Substances

Nuclear Proteins
Transcription Factors

Grants and funding

No. 81872467 and 82073880/National Natural Science Foundation of China (National Science Foundation of China)