Background <p>Breast cancer (BC) is the most prevalent cancer diagnosed in women across the globe and is the main factor behind cancer-related deaths in women. There is an increasing amount of evidence, suggesting that tumor microenvironment is controlled by tumor-associated macrophages (TAMs) and exosomes. Nevertheless, the precise mechanism of TAMs-derived exosomes to regulate the advancement of BC is not entirely clear.</p> Methods <p>The proliferation, migration, invasion, apoptosis, glycolysis, and the level of reactive oxygen species (ROS) in BC cells were evaluated using EdU, Transwell assays, flow cytometry, and corresponding kits. RT-qPCR and western blotting were employed to examine mRNA and protein expression. Exosomes were isolated from TAMs culture supernatant and confirmed through transmission electron microscopy, western blotting, and immunofluorescence assay. Bioinformatics, dual-luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay were utilized to determine the binding of IRF9 to the IFI6 promoter. A mouse xenograft model was established for in vivo analysis. Transcriptomic analysis was conducted on a pre-selected interferon-related gene set, which may limit the discovery of other relevant genes and pathways.</p> Results <p>Interferon alpha-inducible protein 6 (IFI6) was highly expressed in TAMs-originated exosomes. TAMs promoted BC cells’ proliferation, migration, invasion, and glycolysis through the transmission of exosomal IFI6 while inhibiting apoptosis and ROS accumulation. Interferon regulatory factor 9 (IRF9) promoted IFI6 transcription in TAMs. Mechanistically, IRF9 in TAMs-secreted exosomes promoted the function of BC cells by mediating IFI6. Furthermore, TAMs-derived exosomes influenced the growth of BC tumors by regulating the IRF9/IFI6 axis in vivo.</p> Conclusion <p>Generally, TAMs-derived exosomes could promote BC progression via the&#xa0;IRF9/IFI6 axis.</p>