AbstractBackgroundExosomes are critical mediators of tumor cell‐microenvironment cross talk. However, the mechanisms by which hypoxic Lung adenocarcinoma (LUAD)‐derived exosomes modulate macrophage polarization remain largely unknown. The aim of this study was to investigate the effects of hypoxic LUAD‐derived exosome on macrophage polarization and explore the underlying molecular mechanism.Materials and methodsLUAD‐derived exosomes were isolated, and then confirmed by transmission electron microscopy, nanoparticle tracking analysis, and Western blot. Internalization of exosomes in macrophages was detected by confocal microscope. Gain‐ and loss‐of‐function experiments, rescue experiments, and xenograft models were performed to uncover the underlying mechanisms of exosomal miR‐1290 induced macrophage polarization in vitro and in vivo.ResultsmiR‐1290 was enriched in hypoxic LUAD cancer cell‐derived exosomes and could be transferred to macrophages. Overexpression of miR‐1290 in macrophages‐induced polarization of M2 phenotype. Luciferase assay verified SOCS3 was the target of miR‐1290. Hypoxic LUAD cell‐derived exosomal miR‐1290 activated the STAT3 signaling pathway by targeting SOCS3 to promote M2 macrophage polarization.ConclusionHypoxic LUAD cells generate miR‐1290‐rich exosomes that promote M2 polarization of macrophages. Targeting exosomal miR‐1290 may provide a potential immunotherapeutic strategy for LUAD.