Epidermal growth factor receptor variant III (EGFRvIII) confers growth advantage to glioblastoma multiforme (GBM) and is associated with significantly shorter survival in GBM patients. The interaction between tumor cells and macrophages plays a crucial role in tumor development, supporting angiogenesis, nurturing tumor stem cells, and promoting immune-suppressive TME. Therefore, elucidating the potential mechanisms by which EGFRvIII mutation in GBM cells regulates surrounding immune cells to drive tumor progression may provide new targets for precise immune therapy for specific GBM subtypes or genotypes. In this study, we found that EGFRvIII was the most common form of EGFR mutation, with an incidence rate of 22.13% in glioma patients and 33.3% in GBM patients. Mechanistically, we found for the first time that EGFRvIII-positive GBM secretes high levels of MDK via the ERK-c-Fos signaling pathway. Subsequently, GBM cell-secreted MDK drives macrophage polarization towards the M2 phenotype and secretion of the cytokine CXCL1 via activation of the macrophage surface receptor LRP1 and downstream pathways. In turn, these macrophages secrete CXCL1, which attracts immune-suppressive cells and TAMs to support GBM growth. In the intracranial glioma model, blocking MDK signaling pathway could inhibit macrophage polarization towards the M2 phenotype and tumor malignant progression. In summary, our study for the first time found that EGFRvIII-positive GBM can drive macrophage polarization towards M2 phenotype and secretion of immune-suppressive cytokine CXCL1 via the c-Fos-MDK-LRP1 signaling pathway, providing new targets for precise immune therapy for specific GBM subtypes or genotypes.