Progranulin Promotes Glioblastoma Malignancy and Immunosuppression via M2-TGF-β Axis: Therapeutic Efficacy of SORT1-Loaded HAMA Hydrogel Microspheres

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, characterized by rapid progression, therapeutic resistance, and a complex immunosuppressive tumor microenvironment (TME). Progranulin (GRN), a secreted glycoprotein implicated in various cancers, plays an underexplored role in GBM. This study investigates GRN's contributions to GBM malignancy and TME modulation, aiming to identify novel therapeutic targets. Integrated bioinformatics analyses of GEO (GSE90598) and TCGA datasets revealed significant GRN upregulation in GBM tissues, correlating with poor overall and progression-free survival (p < 0.05, HR > 1). GRN expression showed strong positive associations with M2 macrophage marker CD163 at both protein (IHC, R = 0.56, p < 0.001) and mRNA levels (TCGA, R = 0.53, p < 0.001). CIBERSORT and ESTIMATE analyses indicated elevated M2 macrophage infiltration and higher immune/stromal scores in high-GRN groups, underscoring GRN's role in fostering immunosuppression. In vitro, GRN knockdown (siGRN) in GBM cell lines (A172) significantly suppressed proliferation (CCK-8), migration (scratch assay), invasion (Transwell), and clonogenicity (p < 0.05). Coculture with macrophages demonstrated that siGRN shifted polarization from M2 (CD206⁺) to M1 (CD86⁺), reducing immunosuppressive cytokines IL-10 and TGF-β1. Transwell assays confirmed GRN's macrophage-dependent promotion of GBM invasion, abrogated by TGF-β receptor inhibitor LY3200882, highlighting the GRN-TGF-β-macrophage axis. In vivo, SORT1-loaded hyaluronic acid methacryloyl (HAMA) hydrogel microspheres, fabricated via microfluidics (70-90 μm diameter, 6-day degradation), were intratumorally injected into nude mouse GBM xenografts. This significantly inhibited tumor growth compared to controls (p < 0.05), demonstrating GRN-targeted therapy's potential. Collectively, GRN drives GBM aggressiveness and TME immunosuppression via M2 polarization and TGF-β signaling. Utilizing SORT1-loaded HAMA microspheres to target and clear GRN proteins provides a promising postoperative treatment strategy for inhibiting GBM recurrence and improving prognosis.