Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
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.
Nat Commun. 2024 Jan 2;15(1):131. doi: 10.1038/s41467-023-44576-2.
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.
溶瘤病毒治疗在癌症治疗中具有广阔的前景，但决定其溶瘤活性的因素仍不清楚。中性粒细胞胞外诱捕网（NETs）与癌症的进展有关，但它们的形成机制及其在溶瘤病毒治疗中的作用仍不清楚。在这项研究中，我们证明在神经胶质瘤中，IGF2BP3 的上调增强了 E3 泛素蛋白连接酶 MIB1 的表达，通过泛素-蛋白酶体途径促进 FTO 的降解。这导致 m6A 介导的 CSF3 释放和 NET 形成增加。溶瘤单纯疱疹病毒（oHSV）刺激恶性神经胶质瘤中 IGF2BP3 诱导的 NET 形成。在雌性小鼠的神经胶质瘤模型中，BET 抑制剂通过阻止 IGF2BP3 诱导的 NET 细胞凋亡来增强 oHSV 的溶瘤活性，通过 BRD4 与 CDK9/RPB-1 复合物招募到 HSV 基因启动子，增强病毒复制。我们的研究结果揭示了 m6A 介导的 NET 形成的调控，强调了溶瘤病毒诱导的 NET 细胞凋亡作为阻碍溶瘤潜能的关键检查点，并提出了将 NET 细胞凋亡作为克服溶瘤病毒治疗中耐药性的一种策略。
