Progranulin promotes glioma progression through the M2-TGF-β axis: targeted therapy with SORT1-loaded HAMA hydrogel...

Glioblastoma (GBM) is the most aggressive primary brain tumor, and is characterized by rapid growth, therapeutic resistance, and a highly immunosuppressive tumor microenvironment (TME). Progranulin (GRN/PGRN), a secreted glycoprotein, promotes malignancy in various cancers, yet its role in GBM remains poorly defined. Bioinformatics analysis of GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) datasets revealed that GRN expression is significantly upregulated in GBM and is associated with shorter overall survival and progression-free survival. High GRN levels correlated strongly with increased M2 macrophage infiltration (marked by CD163 expression) and elevated immune and stromal scores, suggesting that GRN contributes to an immunosuppressive TME. In vitro, silencing GRN in GBM cells markedly inhibited cell proliferation, migration, invasion, and colony formation. Coculture assays demonstrated that GRN knockdown reduced GBM-induced M2 macrophage polarization (CD206⁺) while increasing M1 polarization (CD86⁺), accompanied by decreased secretion of the immunosuppressive cytokines IL-10 and TGF-β. Transwell experiments further showed that GRN promoted GBM invasion in a macrophage-dependent manner via the TGF-β pathway, an effect that was abrogated by the TGF-β receptor I inhibitor LY3200882. We developed SORT1-loaded hyaluronic acid methacrylate (HAMA) hydrogel microspheres to target GRN therapeutically. SORT1 competitively binds to GRN, reducing its concentration in the TME. Intratumoral injection of these microspheres significantly suppressed GBM xenograft growth in vivo. Collectively, our findings identify GRN as a key driver of GBM progression and TME immunosuppression through M2 macrophage polarization and TGF-β signaling. Targeting GRN with SORT1-loaded HAMA microspheres represents a promising adjuvant therapeutic strategy for GBM.