胶质母细胞瘤（GBM）是最具侵袭性的胶质瘤形式，尽管经过强化治疗，复发率仍然很高。肿瘤复发与放射抗性密切相关，而放射抗性又与缺氧有关。在这里，我们利用来自人类 GBM 患者的公开批量、单细胞和空间解析转录组数据发现缺氧和局部补体信号传导之间存在密切联系。补体成分 3 (C3) 和受体 C3AR1 均与人类神经胶质瘤的侵袭性疾病和较短的生存期相关。在 GBM 基因工程小鼠模型中，我们特别在缺氧肿瘤区域发现了 C3。在体外，我们发现几种 G​​BM 和基质细胞类型在缺氧时 C3 和 C3AR1 表达呈氧水平依赖性增加。 C3a 以 C3aR 依赖性方式诱导培养的小胶质细胞和巨噬细胞的 M2 极化。使用拮抗剂 SB290157 靶向 C3aR 可以延长患有神经胶质瘤的小鼠的存活时间，无论是单独使用还是与放射治疗联合使用，同时减少 M2 极化巨噬细胞的数量。我们的研究结果建立了 GBM 中缺氧和补体途径之间的密切联系，并支持缺氧诱导的 C3a-C3aR 信号通过调节巨噬细胞极化而促进神经胶质瘤侵袭性的作用。

Glioblastoma (GBM) is the most aggressive form of glioma with a high rate of relapse despite intensive treatment. 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 human GBM patients. Complement component 3 (C3) and the receptor C3AR1 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-dependent increase in C3 and C3AR1 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.