Abstract

The immunosuppressive tumor microenvironment (TME) is a major issue in the malignant progression of glioma patients. The membrane spanning four domains A4A (MS4A4A) has a relationship with M2 polarization of macrophages, and participates in the malignant progression of various cancers. Therefore, exploration of the key role of MS4A4A contributing to glioma biological processes is urgently needed. We performed the bioinformatics analysis of M2 gene expression and built a model predicting the prognosis of glioma patients. Knocking down or overexpressing MS4A4A was achieved in macrophages, and we identified the polarization of macrophages with different MS4A4A expression levels. In vitro and in vivo experiments were used to investigate the role of MS4A4A in regulating M2 polarization and contributing to malignant behaviour in glioma. We found that MS4A4A was associated with the macrophages' M2 scores and the prognosis of GBM patients. MS4A4A had a higher expression level in M2 polarization macrophages. MS4A4A regulates macrophage M2 polarisation through NF-κB and JAK-STAT6 signalling pathways. Macrophages with MS4A4A overexpression promoted the proliferation, invasion, and TMZ-resistance of glioma cells in vitro and in vivo experiments. The treatment targeting the MS4A4A/ NF-κB/STAT6 axis could improve the prognosis and TMZ-resistance in the glioma mouse model. The present study revealed the novel mechanism of the MS4A4A regulating macrophages M2 polarization, contributing to the formation of immunosuppressive tumor microenvironment in glioma through NF-κB/STAT6 signaling pathways, which promotes the malignant biological process of glioma cells. Our results provided new evidence that NF-κB and STAT6 inhibitors might be a potential adjuvant agent in overcoming MS4A4A-mediated chemotherapy resistance in glioma.