TMIC-86. THE ROLE AND THERAPEUTIC RESEARCH OF NETS IN PROMOTING TMZ RESISTANCE IN GLIOBLASTOMA

Abstract OBJECTIVE This study aims to investigate the issue of resistance to temozolomide (TMZ) treatment in high-grade glioblastoma (GBM), specifically the association between TMZ resistance, the tumor microenvironment (TME), and neutrophil activity. The research hypothesis posits that changes in neutrophils induced by TMZ treatment, particularly the formation of neutrophil extracellular traps (NETs), may lead to TMZ resistance in GBM cells. METHODS The study utilized clinical data analysis and animal model research to evaluate changes in neutrophils during TMZ treatment and their impact on treatment efficacy. Proteomics analysis and high-throughput sequencing were employed to investigate the effect of TMZ on cytokine secretion by GBM cells and how these cytokines stimulate the release of NETs. Additionally, gene ontology (GO) analysis and bioinformatics methods were used to study how NETs promote the epithelial-mesenchymal transition (EMT) process and TMZ resistance by activating specific signaling pathways such as Jak-Stat3. RESULTS The study found that TMZ treatment led to increased neutrophil infiltration, which was associated with poor prognosis in GBM patients. TMZ treatment altered the levels of cytokines secreted by GBM cells, particularly IL-6, promoting the release of NETs by neutrophils. The formation of NETs was closely related to the activation of Stat3 signaling and the promotion of the EMT process in tumor cells, thereby enhancing TMZ resistance. Magnesium-based micromotors were found to improve TMZ efficacy by scavenging ROS production in neutrophils, inhibiting the release of NETs. CONCLUSION This study confirms the association between TMZ resistance and neutrophil activity, particularly the role of NETs in promoting EMT and resistance. These findings provide new insights into the treatment of GBM and offer a theoretical basis for the development of therapeutic strategies targeting NETs, which may improve the response of glioblastoma to TMZ treatment by inhibiting ROS production. The development of this novel therapeutic approach offers new treatment options for postoperative chemotherapy in GBM.