Clusterin-mediated polarization of M2 macrophages: a mechanism of temozolomide resistance in glioblastoma stem cells.

Abstract

Glioblastoma remains one of the most lethal malignancies, largely due to its resistance to standard chemotherapy such as temozolomide. This study investigates a novel resistance mechanism involving glioblastoma stem cells (GSCs) and the polarization of M2-type macrophages, mediated by the extracellular vesicle (EV)-based transfer of Clusterin. Using 6-week-old male CD34⁺ humanized huHSC-(M-NSG) mice (NM-NSG-017) and glioblastoma cell lines (T98G and U251), we demonstrated that GSC-derived EVs enriched with Clusterin induce M2 macrophage polarization, thereby enhancing temozolomide resistance in glioblastoma cells. Single-cell and transcriptome sequencing revealed close interactions between GSCs and M2 macrophages, highlighting Clusterin as a key mediator. Our findings indicate that Clusterin-rich EVs from GSCs drive glioblastoma cell proliferation and resistance to temozolomide by modulating macrophage phenotypes. Targeting this pathway could potentially reverse resistance mechanisms, offering a promising therapeutic approach for glioblastoma. This study not only sheds light on a critical pathway underpinning glioblastoma resistance but also lays the groundwork for developing therapies targeting the tumor microenvironment. Our results suggest a paradigm shift in understanding glioblastoma resistance, emphasizing the therapeutic potential of disrupting EV-mediated communication in the tumor microenvironment.