Glioma promotes macrophage immunosuppressive phenotype through ANXA1 in a methionine metabolism-dependent manner

In gliomas, particularly in glioblastoma (GBM), the tumor immunosuppressive microenvironment is widely recognized as a significant obstacle to effective treatment, contributing to reduced survival rates and the failure of targeted therapies and chemotherapy. Methionine (Met) is an essential amino acid in human metabolism and plays a crucial role in the development of glioma. However, the role of Met metabolism in the formation of the tumor immunosuppression microenvironment remains uncertain. In this study, we investigated the feature of Met metabolism in gliomas and its relationship with the tumor immune microenvironment. First, we began with the overall cohort of glioma patients. Through methionine metabolism activity scoring (MMA-score) of glioma cohorts, we observed a significant positive correlation between MMA-score and glioma WHO grades. Further analysis revealed that tumors with high MMA-scores exhibit more immunosuppressive microenvironment characteristics, including significantly increased infiltration of M2-type macrophages. Subsequently, single-cell RNA sequencing (scRNA-seq) analysis revealed that glioma cells exhibit dominant methionine metabolism activity within the tumor microenvironment, significantly surpassing that of other cell types. This suggests that glioma cells are likely the primary contributors to the overall methionine metabolic activity observed in tumors. Moreover, distinct heterogeneity in methionine metabolism was observed among glioma cells of different grades, indicating that metabolic reprogramming may be associated with tumor malignancy progression. Building upon this, we further focused on GBM and observed that GBM cells with high Met metabolism exhibit more astrocyte-like (AC-like) and mesenchymal-like (MES-like) molecular subtypes. This suggests that these cells may possess enhanced capabilities such as rapid proliferation, metabolic reprogramming, and immune inhibition. Additionally, our study suggested that GBM cells with high Met metabolism activate the ANNEXIN pathway to enhance interaction with macrophages via upregulating ANXA1 expression. Further in vitro experiments suggest that depriving Met supply significantly reduces ANXA1 expression in GBM cells and inhibits M2 polarization of macrophages, underscoring the critical role of Met metabolism in GBM immune regulation. Overall, methionine metabolism emerges as a promising biomarker for glioma grading, with its activity levels significantly associated with tumor malignancy and an immunosuppressive microenvironment.