M2 Macrophages Induce Glioblastoma Ferroptosis Resistance by Suppressing `NCOA4` and Enhancing `FTH1` Expression

Glioblastoma (GBM) is an aggressive brain tumor characterized by significant intratumoral heterogeneity and an immunosuppressive microenvironment, leading to profound therapeutic resistance and poor patient prognosis. Current standard-of-care treatments often fail due to the tumor's adaptability and the protective nature of the blood-brain barrier. While tumor-associated macrophages (TAMs) and ferroptosis (an iron-dependent form of programmed cell death) are known to influence glioma progression, the precise functional interplay between these two mechanisms, particularly how TAMs might contribute to ferroptosis resistance, has remained largely unexplored. Understanding this crosstalk could reveal novel therapeutic targets.

Researchers integrated multi-omics data, including bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomics, from public cohorts to identify ferroptosis-related genes associated with monocyte/macrophage infiltration in glioblastoma. They employed machine learning to develop a 28-gene prognostic signature. Single-cell analysis was used to examine ferroptosis-related gene expression within glioma-infiltrating monocytes/macrophages. Mechanistically, in vitro studies investigated how M2-polarized macrophages influenced GBM cell ferroptosis. Finally, an in vivo model involved co-implantation of M2 macrophages with GBM cells, followed by treatment with the ferroptosis inducer erastin to assess its tumor-suppressive effect.

Multi-omics analysis revealed a strong correlation between ferroptosis-related genes and monocyte/macrophage infiltration in glioblastoma, leading to a robust 28-gene prognostic signature. Single-cell data further showed elevated expression of these ferroptosis-related genes specifically within glioma-infiltrating monocytes/macrophages. Mechanistically, M2-polarized macrophages were found to directly confer ferroptosis resistance to GBM cells. This resistance was achieved by M2 macrophages suppressing the expression of NCOA4 (nuclear receptor coactivator 4) and simultaneously enhancing the expression of FTH1 (ferritin heavy chain 1). This dual action effectively reduced labile iron release within GBM cells, a critical step in ferroptosis initiation.

In vivo, the co-implantation of M2 macrophages completely abrogated the tumor-suppressive effect of the ferroptosis inducer erastin, demonstrating a potent M2 macrophage-mediated resistance mechanism.