Exosomal NEAT1 from tumor stem cells induces SIRPA+ macrophages to enhance immune evasion and glioblastoma progression via upregulating the HSP90B1/STAT3 axis

BACKGROUND: macrophages were induced and exerted their functions in glioblastoma have not been fully elucidated. METHODS: macrophages on proliferation, migration and invasion of tumor cells. CXCL8 secretion by macrophages was quantified with ELISA. Bioinformatic analyses were performed to predict candidate upstream regulators of SIRPA, which were subsequently validated by qPCR, Western blot, RIP, Co-IP, PLA and dual-luciferase assays. Orthotopic xenografts were applied to validate the relevant molecular pathways in vivo. RESULTS: macrophages within tumor parenchyma and their spatial colocalization with GSC markers. GSC-derived exosomes induced SIRPA expression in macrophages and suppressed their phagocytic ability, thereby enhancing proliferation, migration, invasion and EMT of glioblastoma cells. LncRNA NEAT1 was highly expressed in GSCs and their exosomes. NEAT1 was efficiently transferred into macrophages, then stabilized HSP90B1 and strengthened its interaction with STAT3, thereby enhancing HSP90B1-dependent STAT3 phosphorylation and activating SIRPA transcription. In vivo, knockdown of NEAT1 or SIRPA in macrophages partially reversed intracranial tumor progression induced by GSC-derived exosomes and prolonged survival of tumor-bearing mice, supporting the tumor-promoting role of the NEAT1/HSP90B1/STAT3/SIRPA axis in glioblastoma. CONCLUSIONS: phenotype through the HSP90B1/STAT3 axis, thereby promoting immune evasion and progression of glioblastoma, highlighting NEAT1 as a critical mediator of the crosstalk between GSCs and macrophages, which can serve as a potential therapeutic target against glioblastoma.