胶质母细胞瘤（GBM）肿瘤由多个细胞群体组成，包括具有自我更新能力的胶质母细胞瘤干细胞（GSCs）和免疫抑制性微胶质细胞。在这里，我们确定了库尼茨型蛋白酶抑制剂TFPI2作为连接这些细胞群体及其相关的GBM基因特征（干细胞性和免疫抑制性）的关键因子。TFPI2通过激活c-Jun N-末端激酶-信号传导子和转录活化子（STAT）3途径促进GSC的自我更新和肿瘤生长。分泌的TFPI2与其功能性受体CD51在微胶质细胞上相互作用，通过激活STAT6信号转导，触发微胶质细胞的浸润和免疫抑制极化。抑制TFPI2-CD51-STAT6信号轴可以激活T细胞，在GBM小鼠模型中与抗PD1治疗协同作用。在人类GBM中，TFPI2与干细胞性、微胶质细胞数量、免疫抑制和预后不良呈正相关。我们的研究揭示了TFPI2的功能，并支持将其作为GBM的有效靶点进行治疗。©2023. 作者，独家授权给Springer Nature America, Inc.

Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy in GBM mouse models. In human GBM, TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis. Our study identifies a function for TFPI2 and supports therapeutic targeting of TFPI2 as an effective strategy for GBM.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.