神经胶质瘤干细胞（GSC）的原神经间充质（PN-MES）转化可以显着增加增殖、侵袭、化疗耐受性和复发。肿瘤相关巨噬细胞（TAM）的M2样极化具有很强的免疫抑制作用，促进肿瘤恶性和血管生成。对 GSC 和 TAM 之间的相互作用及其相关分子机制的了解有限。本研究通过生物信息学分析、GSC与TAM共培养、TAM极化表型测定等体外实验证实，MES-GSCs分泌的CCL2通过IKZF1-CD84-SHP2途径和PN-促进TAM-M2极化。通过 TAM 中的 IKZF1-LRG1 途径对 GSC 进行 MES 转化。 IKZF1 抑制剂可以显着减少动物神经胶质瘤模型中的肿瘤体积并提高生存率，并抑制 TAM-M2 极化和 GSC 恶性表型。本研究结果表明胶质瘤微环境中 TAM 和 GSC 之间的重要相互作用及其在肿瘤进展中的作用。这些发现还为 TAM 功能和 GSC 恶性表型调节的后续临床转化研究提供了一个新靶标。© 2024。作者，获得 Springer Nature Limited 的独家许可。

The proneural-mesenchymal (PN-MES) transformation of glioma stem cells (GSCs) can significantly increase proliferation, invasion, chemotherapy tolerance, and recurrence. M2-like polarization of tumor-associated macrophages (TAMs) has a strong immunosuppressive effect, promoting tumor malignancy and angiogenesis. There is limited understanding on the interactions between GSCs and TAMs as well as their associated molecular mechanisms. In the present study, bioinformatics analysis, GSC and TAM co-culture, determination of TAM polarization phenotypes, and other in vitro experiments confirmed that CCL2 secreted by MES-GSCs promotes TAM-M2 polarization via the IKZF1-CD84-SHP2 pathway and PN-MES transformation of GSCs via the IKZF1-LRG1 pathway in TAMs. IKZF1 inhibitors could significantly reduce tumor volumes in animal glioma models and improve survival, as well as suppress TAM-M2 polarization and the GSC malignant phenotype. The results of this study indicate the important interaction between TAMs and GSCs in the glioma microenvironment as well as its role in tumor progression. The findings also suggest a novel target for follow-up clinical transformation research on the regulation of TAM function and GSCs malignant phenotype.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.