Tumor-associated macrophages (TAMs) are involved in tumor progression, metastasis, and immunosuppression. Since TAMs are highly plastic and could alter their phenotypes to pro-inflammatory M1 in response to environmental stimuli, re-educating TAMs has emerged as a promising approach to overcoming the challenges of solid cancer treatment. This study investigated the effect of interleukin (IL)-9 on macrophage M1 polarization and verified its antitumor potential to retrain TAMs and promote chemokine secretion. We demonstrated that IL-9 stimulated macrophage proliferation and polarized them toward the pro-inflammatory M1 phenotype in an IFN-γ-dependent manner. Tumor-localized IL-9 also polarized TAMs toward M1 in vivo and made them release CCL3/4 and CXCL9/10 to recruit antitumor immune cells, including T and NK cells, into the tumor microenvironment. Furthermore, peritoneal treatment with recombinant IL-9 delayed the growth of macrophage-enriched B16F10 melanoma and 4T1 breast cancer in syngeneic mice, although IL-9 treatment did not reduce tumor growth in the absence of macrophage enrichment. These results demonstrate the efficacy of IL-9 in macrophage polarization to trigger antitumor immunity.
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