FSTL1 sustains glioma stem cell stemness and promotes immunosuppressive macrophage polarization in glioblastoma.

Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) play a crucial role in glioblastoma (GBM) progression by interacting with glioma stem cells (GSCs). These interactions lead to the polarization of TAMs toward an M2 phenotype, which, in turn, enhances the stem-like traits and malignant progression of GSCs. Our study shows that FSTL1, a protein released by GSCs, is significantly elevated in gliomas and linked to the progression of the disease. By suppressing FSTL1 in a mouse model, we observed reduced tumor growth and a decrease in M2 macrophages. In vitro studies show that FSTL1 from GSCs promotes M2 polarization and infiltration. Importantly, GSCs utilize autocrine FSTL1 to interact with TLR2, which inhibits the endocytosis-lysosomal degradation pathway mediated by EGFR, resulting in the activation of the PI3K-AKT signaling pathway that is critical for maintaining their self-renewal. These findings underscore the importance of FSTL1 in GSC maintenance and M2 macrophage polarization, suggesting that interventions targeting the FSTL1/TLR2 pathway could provide a novel therapeutic approach for GBM patients.