Simple SummaryThe role of complement in cancer has raised much attention over the last decade. Recent studies have pointed to the tumor-promoting effects of complement activation within the tumor microenvironment of various cancers. The aim of our study was to assess the expression of the complement anaphylatoxin C3a and its receptor C3aR in the context of primary and metastatic brain tumors. We observed a high expression of C3aR in Grade 4 diffuse gliomas, i.e., glioblastoma multiforme,IDH-wildtype (GBM) and astrocytoma,IDH-mutant, Grade 4, compared to less aggressive primary brain tumors and brain metastasis. In GBM, C3aR was detected in tumor-associated macrophages, which also expressed VEGF, suggesting pro-angiogenic and tumor growth-supporting activities. In addition, robust levels of C3a were detected in GBM. Lastly, our results pointed to the critical role of TGF-β in the regulation of C3a and C3aR expression. Besides providing novel insights into glioma pathogenesis, our findings open new therapeutic avenues (C3aR antagonists) for this lethal disease.AbstractThe complement (C) innate immune system has been shown to be activated in the tumor microenvironment of various cancers. The C may support tumor growth by modulating the immune response and promoting angiogenesis through the actions of C anaphylatoxins (e.g., C5a, C3a). The C has important double-edged sword functions in the brain, but little is known about its role in brain tumors. Hence, we analyzed the distribution and the regulated expression of C3a and its receptor C3aR in various primary and secondary brain tumors. We found that C3aR was dramatically upregulated in Grade 4 diffuse gliomas, i.e., glioblastoma multiforme,IDH-wildtype (GBM) and astrocytoma,IDH-mutant, Grade 4, and was much less expressed in other brain tumors. C3aR was observed in tumor-associated macrophages (TAM) expressing CD68, CD18, CD163, and the proangiogenic VEGF. Robust levels of C3a were detected in the parenchyma of GBM as a possible result of Bb-dependent C activation of the alternative C pathway. Interestingly, in vitro models identified TGF-β1 as one of the most potent growth factors that upregulate VEGF, C3, and C3aR in TAM (PMA-differentiated THP1) cell lines. Further studies should help to delineate the functions of C3a/C3aR on TAMs that promote chemotaxis/angiogenesis in gliomas and to explore the therapeutic applications of C3aR antagonists for brain tumors.