Abstract

Neutrophil extracellular traps (NETs) are increasingly recognized for their critical roles in tumor progression and tumor immune microenvironment (TIME) modulation, yet their functions in glioma remain incompletely understood. Leveraging 68 NET-associated regulators, we identified two distinct NET-based molecular subtypes. The G1 subtype exhibited an elevated NET expression profile, immunosuppressive TIME, and was associated with unfavorable patient outcomes. MMP9, TLR8, and LILRB2 were pinpointed as key regulators and a prognostic model was constructed with robust predictive performance. These regulators could promote NET formation, suppress T-cell activity and facilitate immune evasion in glioma. Mechanistically, the NEAT1 / miR-149-5p / MMP9 , TLR8 and LILRB2 axis demonstrated to promote glioma progression. Patients with high expression levels of these regulators were predicted to correlate with better chemotherapy response but poorer immunotherapy outcomes. In summary, our results identify MMP9, TLR8, and LILRB2 as pivotal regulators of glioma malignancy and TIME remodeling, with significant implications for prognosis and the development of targeted therapies.