Metabolic-transcriptional rewiring by NFE2L2 promotes M2 macrophage polarization and anti-PD-L1 resistance in glioma

Glioma is a highly malignant brain tumor, and its characteristic immunosuppressive microenvironment is closely associated with poor patient prognosis. In this study, we aimed to investigate the regulatory role of the transcription factor NFE2L2 (nuclear factor erythroid 2-related factor 2) in glioma and its underlying molecular mechanisms. Analysis based on the TCGA database and clinical samples revealed that NFE2L2 is significantly overexpressed in glioma tissues, and its expression level is closely correlated with tumor immune infiltration, particularly showing a positive association with M2-like tumor-associated macrophage (TAM) infiltration. By establishing an in vitro TAM induction model, we observed that NFE2L2 expression was upregulated during M2-like macrophage polarization. Further gene overexpression experiments demonstrated that NFE2L2 significantly enhances the migratory and invasive capabilities of glioma cells. To explore its in vivo function, we constructed an NFE2L2-deficient mouse model. The results showed that NFE2L2 deficiency led to the remodeling of the tumor immune microenvironment, thereby significantly improving the therapeutic response to PD-1 immune checkpoint inhibitors and suppressing glioma progression. Combined transcriptomic and metabolomic analyses identified differential genes and metabolites associated with NFE2L2, revealing its critical role in promoting M2-like macrophage polarization and modulating the tumor microenvironment. In summary, NFE2L2 not only plays a pivotal role in glioma development but may also serve as a potential therapeutic target. Future studies will further explore the specific mechanisms by which NFE2L2 regulates macrophage polarization and its clinical application prospects in immunotherapy.