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Tumor recurrence is tightly linked to radio-resistance, which in turn is associated with hypoxia. Here, we discovered a strong link between hypoxia and local complement signaling using publicly available bulk, single-cell, and spatially resolved transcriptomic data from patients with GBM. Complement component 3 (\n                    <jats:italic>C3<\/jats:italic>\n                    ) and the receptor\n                    <jats:italic>C3AR1<\/jats:italic>\n                    were both associated with aggressive disease and shorter survival in human glioma. In a genetically engineered mouse model of GBM, we found C3 specifically in hypoxic tumor areas. In vitro, we found an oxygen level\u2013dependent increase in\n                    <jats:italic>C3<\/jats:italic>\n                    and\n                    <jats:italic>C3AR1<\/jats:italic>\n                    expression in response to hypoxia in several GBM and stromal cell types. C3a induced M2 polarization of cultured microglia and macrophages in a C3aR-dependent fashion. Targeting C3aR using the antagonist SB290157 prolonged survival of glioma-bearing mice both alone and in combination with radiotherapy while reducing the number of M2-polarized macrophages. Our findings establish a strong link between hypoxia and complement pathways in GBM and support a role of hypoxia-induced C3a\/C3aR signaling as a contributor to glioma aggressiveness by regulating macrophage polarization.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.179854","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T12:07:55Z","timestamp":1724328475000},"source":"Crossref","is-referenced-by-count":45,"title":["Hypoxia-induced complement component 3 promotes aggressive tumor growth in the glioblastoma microenvironment"],"prefix":"10.1172","volume":"9","author":[{"given":"Rebecca","family":"Rosberg","sequence":"first","affiliation":[{"name":"Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University Cancer Centre, Lund University, Lund, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina I.","family":"Smolag","sequence":"additional","affiliation":[{"name":"Division 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