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

Tumor-associated macrophages are an abundant, tumor-infiltrating cell population that supports the evasion of tumor cells from antitumoral immune cell detection by generating an immunosuppressive tumor-immune microenvironment (TIME). The immunosuppressive function of macrophages is dictated by the cytokine environment. IL-9 is a pleiotropic cytokine that can be a positive or negative regulator of tumor growth. Our lab previously identified a protumoral role of IL-9 by expanding lung interstitial macrophage (IM) populations and inducing the expression of arginase 1 (ARG1) to enhance tumor growth. However, the underlying mechanism by which IL-9 receptor/ARG1+ IMs promote tumor progression remains incomplete. Here, we demonstrate that macrophage-targeting nanoparticles containing Arg1 siRNA can therapeutically reduce tumor burden and reduce protumor arginine-derived metabolite production. Furthermore, using bulk RNA sequencing of lung macrophages isolated from Il9r-/-:wild-type mixed-bone marrow chimeric mice, we demonstrate that IL-9 intrinsically alters the transcriptomic landscape of lung IMs. Mechanistically, IL-9 promotes intrinsic Arg1 expression through an IRF4-dependent regulatory pathway and modulates arginine and polyamine concentration within IMs and lung tissue, resulting in increased lung tumor growth and altered macrophage phenotypes. Thus, our work defines a protumor function of IL-9-responsive macrophages mediated by altered intrinsic arginine metabolism in lung IMs that enhances lung tumor growth.