Isocitrate dehydrogenase (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 GBM'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. Significance: GBM progression could be induced by hypoxia via the HIF1A–FOSL2 axis. Tumor-derived ANXA1 is associated with recruitment and polarization of bone marrow–derived macrophages to suppress the immunoenvironment. The polarized macrophages promote tumor cell NES transition and migration. This article is highlighted in the In This Issue feature, p. 2711

中文翻译：

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胶质母细胞瘤肿瘤与免疫环境的自然协同进化

异柠檬酸脱氢酶 (IDH) 野生型胶质母细胞瘤 (GBM) 的预后较差。更好地了解肿瘤进化是开发更有效治疗方法的关键。在这里，我们通过使用罕见的多焦点样本来研究 GBM 的自然进化轨迹。我们对来自 8 个多灶性 IDH 野生型原发性 GBM 的 61,062 个单细胞进行了测序，并定义了肿瘤的自然进化特征 (NES)。我们发现 NES 与调节大脑发育的转录因子（包括 MYBL2 和 FOSL2）的激活显着相关。缺氧可能通过激活 HIF1A-FOSL2 轴参与诱导 NES 转变。高 NES 肿瘤细胞可以通过激活 FOSL2-ANXA1-FPR1/3 轴来招募和极化骨髓来源的巨噬细胞。这些极化的巨噬细胞可以有效抑制T细胞活性并加速肿瘤细胞中的NES转变。此外，极化的巨噬细胞可以上调CCL2以诱导肿瘤细胞迁移。意义：缺氧可通过 HIF1A-FOSL2 轴诱导 GBM 进展。肿瘤源性 ANXA1 与骨髓源性巨噬细胞的招募和极化相关，以抑制免疫环境。极化的巨噬细胞促进肿瘤细胞NES转变和迁移。这篇文章在本期特稿中重点介绍，第 17 页。2711 肿瘤源性 ANXA1 与骨髓源性巨噬细胞的招募和极化相关，以抑制免疫环境。极化的巨噬细胞促进肿瘤细胞NES转变和迁移。这篇文章在本期特稿中重点介绍，第 17 页。2711 肿瘤源性 ANXA1 与骨髓源性巨噬细胞的招募和极化相关，以抑制免疫环境。极化的巨噬细胞促进肿瘤细胞NES转变和迁移。这篇文章在本期特稿中重点介绍，第 17 页。2711