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. Here, CXCL1 is linked to glioblastoma.