Hypoxia-driven protease legumain promotes immunosuppression in glioblastoma.

ABSTRACT: Glioblastoma (GBM) is a hypoxic and "immune-cold" tumor containing rich stromal signaling molecules and cell populations, such as proteases and immunosuppressive tumor-associated macrophages (TAMs). Here, we seek to profile and characterize the potential proteases that may contribute to GBM immunosuppression. Legumain (LGMN) emerges as the key protease that is highly enriched in TAMs and transcriptionally upregulated by hypoxia-inducible factor 1-alpha (HIF1α). Functionally, the increased LGMN promotes TAM immunosuppressive polarization via activating the GSK-3β-STAT3 signaling pathway. Inhibition of macrophage HIF1α and LGMN reduces TAM immunosuppressive polarization, impairs tumor progression, enhances CD8⁺ T cell-mediated anti-tumor immunity, and synergizes with anti-PD1 ther

SUBMITTER: Pang L 

PROVIDER: S-EPMC10694605 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature