IDH wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study glioblastoma's natural evolutionary trajectory by using rare, multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES-transition potentially via activation of the HIF1A-FOSL2 axis. High NES tumor cells could recruit and polarize bone marrow-derived macrophages through activation of the FOSL2-ANXA1-FPR1/3 axis. These polarized macrophages can efficiently suppress T cell activity and accelerate NES-transition in tumor cells. Moreover, The polarized macrophages could upregulate CCL2 to induce tumor cell migration.

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