Targeting the tumor microenvironment: reprogramming macrophages as a novel therapeutic strategy in FUOM-deficient glioblastoma

Glioma, the most prevalent CNS malignancy and generally poor prognosis, is characterized by a highly immunosuppressive tumor microenvironment. Fucose mutarotase (FUOM) is a known rockulose mutase secretion protein involved in pathological immune remodeling. However, the precise role of FUOM involvement in glioma has yet to be elucidated. Herein, we delineated FUOM expression using multiplex-immunohistochemistry on tissue microarrays, and its prognostic predictive value was assessed using the Cox regression method. Then we investigated the altered proliferation, migration, and invasion capabilities of glioma cells upon regulated FUOM expression in vitro. Chemokine antibody microarray, immunoassay, and Co-IP were employed to detect interactions between macrophages and glioma cells. In addition, the in vivo therapeutic effects of FUOM were confirmed using animal subcutaneous glioma models. FUOM was highly expressed in glioma tissues and correlated with aggressive glioma progression and unfavorable patient prognosis. Macrophage infiltration into the glioma TME was observed upon FUOM downregulation, with induced CXC motif chemokine ligand-13 (CXCL13) release in maintaining M2-like phenotype. In addition, conditioned media from FUOM knockdown glioma cell lines induced M2-like macrophage chemotaxis migration. Finally, blocking FUOM expression on glioma models enhanced M2-like macrophage phenotype and increased chemotactic migration both in vivo and in vitro. Collectively, our work reveals that FUOM induces M2-like macrophage polarization and promotes glioma progression by mediating CXCL13 secretion.