Macrophage-intrinsic and IL-9-dependent arginine metabolism promotes lung tumor growth

Furthermore, using bulk RNA sequencing of lung macrophages isolated from Il9r-/-:WT mixed-bone marrow chimeric mice, we demonstrate that IL-9 intrinsically alters the transcriptomic landscape of lung interstitial macrophages. Mechanistically, IL-9 promotes intrinsic Arg1 expression through an IRF4-dependent regulatory pathway and modulates arginine and polyamine concentration within interstitial macrophages and lung tissue, resulting in increased lung tumor growth and altered macrophage phenotypes.

Thus, our work defines a pro-tumor mechanism of IL-9-responsive macrophages mediated by altered intrinsic arginine metabolism in lung interstitial macrophages that enhances lung tumor growth.