Kunitz-type protease inhibitor TFPI2 remodels stemness and immunosuppressive tumor microenvironment in glioblastoma

Nat Immunol. 2023 Oct;24(10):1654-1670. doi: 10.1038/s41590-023-01605-y. Epub 2023 Sep 4.


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.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Glioblastoma* / metabolism
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Mice
  • Neoplastic Stem Cells / metabolism
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use
  • Signal Transduction
  • Tumor Microenvironment


  • Protease Inhibitors
  • Carrier Proteins
  • Immunosuppressive Agents