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Exosomes participate in intercellular communication and glioma microenvironment modulation, but the exact mechanisms by which glioma-derived exosomes (GDEs) promote the generation of the immunosuppressive microenvironment are still unclear. Here, we investigated the effects of GDEs on autophagy, the polarization of tumor-associated macrophages (TAMs), and glioma progression. Compared with normoxic glioma-derived exosomes (N-GDEs), hypoxic glioma-derived exosomes (H-GDEs) markedly facilitated autophagy and M2-like macrophage polarization, which subsequently promoted glioma proliferation and migration in vitro and in vivo. Western blot and qRT-PCR analyses indicated that interleukin 6 (IL-6) and miR-155-3p were highly expressed in H-GDEs. Further experiments showed that IL-6 and miR-155-3p induced M2-like macrophage polarization via the IL-6-pSTAT3-miR-155-3p-autophagy-pSTAT3 positive feedback loop, which promotes glioma progression. Our study clarifies a mechanism by which hypoxia and glioma influence autophagy and M2-like macrophage polarization via exosomes, which could advance the formation of the immunosuppressive microenvironment. Our findings suggest that IL-6 and miR-155-3p may be novel biomarkers for diagnosing glioma and that treatments targeting autophagy and the STAT3 pathway may contribute to antitumor immunotherapy.

Hypoxia is a critical factor in the malignant progression of glioma, especially for the highly-invasive mesenchymal (MES) subtype. But the detailed mechanisms in hypoxia-induced glioma MES transition remain elusive. Pseudogenes, once considered to be non-functional relics of evolution, are emerging as a critical factor in human tumorigenesis and progression. Here, we investigated the clinical significance, biological function, and mechanisms of protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P1) in hypoxia-induced glioma MES transition. In this study, we found that PDIA3P1 expression was closely related to tumor degree, transcriptome subtype, and prognosis in glioma patients. Enrichment analysis found that high PDIA3P1 expression was associated with epithelial-mesenchymal transition, extracellular matrix (ECM) disassembly, and angiogenesis. In vitro study revealed that overexpression of PDIA3P1 enhanced the migration and invasion capacity of glioma cells, while knockdown of PDIA3P1 induced the opposite effect. Further studies revealed that PDIA3P1 functions as a ceRNA, sponging miR-124-3p to modulate RELA expression and activate the downstream NF-κB pathway, thus promoting the MES transition of glioma cells. In addition, Hypoxia Inducible Factor 1 was confirmed to directly bind to the PDIA3P1 promotor region and activate its transcription. In conclusion, PDIA3P1 is a crucial link between hypoxia and glioma MES transition through the PDIA3P1-miR-124-3p-RELA axis, which may serve as a prognostic indicator and potential therapeutic target for glioma treatment.