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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\u2013FOSL2 axis. High-NES tumor cells could recruit and polarize bone marrow\u2013derived macrophages through activation of the FOSL2\u2013ANXA1\u2013FPR1\/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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>GBM progression could be induced by hypoxia via the HIF1A\u2013FOSL2 axis. Tumor-derived ANXA1 is associated with recruitment and polarization of bone marrow\u2013derived macrophages to suppress the immunoenvironment. The polarized macrophages promote tumor cell NES transition and migration.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 2711<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-22-0196","type":"journal-article","created":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T15:51:53Z","timestamp":1663602713000},"page":"2820-2837","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":122,"title":["Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma"],"prefix":"10.1158","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4319-7862","authenticated-orcid":false,"given":"Lingxiang","family":"Wu","sequence":"first","affiliation":[{"name":"1The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China."},{"name":"2Department of Bioinformatics, Nanjing Medical University, Nanjing, China."},{"name":"3Institute for Brain Tumors, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6228-0605","authenticated-orcid":false,"given":"Wei","family":"Wu","sequence":"additional","affiliation":[{"name":"1The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China."},{"name":"2Department of Bioinformatics, Nanjing Medical University, Nanjing, China."},{"name":"3Institute for Brain Tumors, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 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