Complement C5a/C5aR1 pathway facilitates glioblastoma progression via fostering glioma stem cell-macrophage symbiosis.

Tumor-associated macrophages (TAMs) symbiotically interact with glioma stem cells (GSCs) to facilitate GSCs stemness maintenance and glioblastoma (GBM) progression. Here we identified the complement 5a (C5a) as a key mediator of GSCs-TAMs symbiosis through integrative screening. C5a is preferentially expressed and secreted by GSCs. C5a activates the p-STAT3-cMyc-PD-L1 axis to promote GSCs proliferation, self-renewal and resistance against cytotoxic T cells through its receptor C5aR1. Moreover, GSCs-derived C5a trigger the infiltration and immunosuppressive polarization of TAMs through C5aR1-p-AKT T308 axis in tumor microenvironment. Importantly, silencing or pharmacological inhibition of C5a/C5aR1 disrupts both GSCs and TAMs and suppresses GBM tumor growth. In human GBM, the C5a/C5aR1 axis is activated and positively correlates with stemness, immunosuppressive TAMs and predicts poor prognosis. Collectively, these results demonstrate the key role of C5a/C5aR1 pathway in GSCs-TAMs symbiosis and indicate the therapeutic potential of targeting this pathway for GBM treatment.