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Tumor-associated macrophages (TAM) are involved in tumor progression, metastasis, and immunosuppression. Because TAMs are highly plastic and could alter their phenotypes to proinflammatory M1 in response to environmental stimuli, reeducating TAMs has emerged as a promising approach to overcoming the challenges of solid cancer treatment. This study investigated the effect of IL9 on macrophage M1 polarization and verified its antitumor potential to retrain TAMs and promote chemokine secretion. We demonstrated that IL9 stimulated macrophage proliferation and polarized them toward the proinflammatory M1 phenotype in an IFNγ-dependent manner. Tumor-localized IL9 also polarized TAMs toward M1 in vivo and made them release CCL3/4 and CXCL9/10 to recruit antitumor immune cells, including T and natural killer cells, into the tumor microenvironment. Furthermore, peritoneal treatment with recombinant IL9 delayed the growth of macrophage-enriched B16F10 melanoma and 4T1 breast cancer in syngeneic mice, although IL9 treatment did not reduce tumor growth in the absence of macrophage enrichment. These results demonstrate the efficacy of IL9 in macrophage polarization to trigger antitumor immunity. Significance: These findings clarified the effect of IL9 on macrophage M1 polarization and verified its antitumor potential through retraining TAMs and chemokine secretion.

FACS gating strategy used for tumor-infiltrating immune cell analysis

Bodyweight change of the tumor-implanted mice in Figure 6

Generation of sorted bone marrow-derived macrophages (BMDMs)

Primers used in this study

Gating strategy to analyze the chemotactic migration of immune cells

Bodyweight change in the tumor-implanted mice in Figure 3

Treatment with IL-9 induces STAT1 and STAT3 phosphorylation in RAW 264.7 cells

Clodronate-encapsulated liposomes show cytotoxicity to BMDMs but not to B16F10 cells

IL-9 promotes M1 polarization of macrophages in vitro

Expression of IL-9R on the surface of B16F10 and 4T1 cells