Abstract Interleukin 4 (IL-4) is a cytokine that, among other actions, can induce macrophages to undergo alternative activation and polarize to M2 macrophages which have been reported to promote tumorigenesis and metastasis. IL-4 also promotes the formation of multinucleated giant cells from macrophages in vitro and participates in the development of the foreign body reaction in vivo. AC2M2 cells, a highly metastatic mouse carcinoma cell line, were transduced with retroviruses expressing IL-4 (IL-4-AC2M2) or empty vector control (EV-AC2M2). Co-culture experiments showed that AC2M2-derived IL-4 polarized macrophages to express the M2 marker, arginase 1. EV- and IL-4-AC2M2 cells grew at the same rate in vitro. However, mice injected with IL-4-AC2M2 cells grew tumors at a significantly reduced rate as compared to control mice injected with EV-AC2M2 cells in an orthotopic mouse mammary tumor engraftment model. IL-4 expression also correlated with elimination of lung metastasis. Reduced primary tumor growth and complete abolishment of lung metastasis in the IL-4 group correlated with a 30-fold increase of tumor associated macrophage populations and macrophage phagocytosis of tumor cells. Thus, tumor-derived IL-4 suppressed tumorigenesis and lung metastasis by activating macrophage phagocytosis in the tumor microenvironment; suggesting that IL-4 could be a good candidate for immunotherapy. Note:This abstract was not presented at the conference. Citation Format: Connie Shengnan Zhang, Peter A. Greer. Tumor cell-derived IL-4 suppresses tumor growth and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B098.