The Role of Progranulin in Glioblastoma Progression and Tumor Microenvironment Modulation

Glioblastoma (GBM) is the most aggressive type of primary brain tumor and is characterized by its invasiveness, therapeutic resistance, and complex tumor microenvironment (TME). Progranulin (GRN), a secreted glycoprotein, has been implicated in promoting malignancy across various cancers, but its role in GBM remains underexplored. This study presents an investigation of the molecular and immunological functions of GRN in GBM progression, with a focus on its ability to regulate tumor cell behavior and TME dynamics. Through integrated bioinformatics analyses using the GEO and TCGA datasets, we identified GRN expression as significantly upregulated in GBM, which was correlated with poor patient survival (p < 0.05, HR > 1). Immunohistochemical and mRNA analyses revealed a strong positive correlation between GRN and the M2 macrophage marker CD163 (R = 0.56 and 0.53, p < 0.001), suggesting that GRN plays a role in promoting an immunosuppressive TME. In vitro experiments demonstrated that GRN knockdown in GBM cell lines (siGRN-GBM) significantly inhibited proliferation, migration, invasion, and clonogenic potential (p < 0.05). Coculture assays further revealed that GRN silencing reduced M2 macrophage polarization (CD206⁺) while increasing M1 polarization (CD86⁺), accompanied by decreased secretion of the immunosuppressive cytokines IL-10 and TGF-β. Transwell assays confirmed that GRN promotes GBM invasion in a macrophage-dependent manner, with the TGF-β receptor I inhibitor LY3200882 abrogating this effect, highlighting the role of the GRN-TGF-β axis in TME regulation. These findings establish GRN as a pivotal driver of GBM malignancy by enhancing tumor cell aggressiveness and fostering an immunosuppressive TME via M2 macrophage polarization.