Background <p>Signal Regulatory Protein Alpha (SIRPA) functions as an inhibitory receptor to suppress phagocytosis of macrophages and promote tumor immune evasion. Recent studies revealed that SIRPA deficiency reprogrammed tumor-associated macrophages toward an antitumor phenotype, and SIRPA functioned independently of CD47. However, the exact role and signaling pathways by which SIRPA⁺ macrophages were induced and exerted their functions in glioblastoma have not been fully elucidated.</p> Methods <p>Public single-cell RNA sequencing datasets were analyzed to identify SIRPA⁺ macrophages and characterize their transcriptional states. Immunofluorescence staining was applied to compare difference in SIRPA expression between tumor and peritumoral tissues, and spatial association of SIRPA⁺ macrophages with glioblastoma stem cells (GSCs) was investigated. Phenotypic alterations of macrophages were assessed after coculture with glioblastoma cells or GSCs. Transwell and CCK-8 assays were performed to evaluate the effects of SIRPA⁺ 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.</p> Results <p>Bioinformatic analysis of single-cell datasets identified a distinct subset of SIRPA⁺ macrophages, enriched in tumor regions with epithelial–mesenchymal transition (EMT) signatures, correlating with poor clinical prognosis. Immunofluorescence confirmed higher abundance of SIRPA⁺ 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.</p> Conclusions <p>GSC-derived exosomal NEAT1 reprogrammed macrophages toward an immunosuppressive SIRPA⁺ 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.</p>