Smyd5 mediates IL-4 epigenetic control of macrophage antigen presentation to drive cooperative T cell-mediated tumor suppression [ATAC-seq]

IL-4 is classically associated with “M2” macrophages considered tumor-immunosuppressive, yet marker-based labels poorly reflect macrophage function in tumors. Reports of a non-canonical, IL-4–imprinted macrophage state (M2inf) with trained-immunity features prompted us to test whether such imprinting contributes to antitumor immunity in vivo. Here we show that, in B16F10 melanoma, IL-4 programs macrophages through the lysine methyltransferase Smyd5 to deposit promoter-proximal H3K36me3, increase MHC class II, and potentiate T cell activation. Myeloid Il4ra deletion increased tumor burden and reduced MHC class II and intratumoral T cell activation, whereas co-transfer of IL-4–primed macrophages suppressed tumors and expanded activated CD4 and CD8 T cells. Antitumor benefit required adaptive lymphocytes and macrophage-intrinsic MHC class II, as Rag1 deficiency or macrophage Rfx5 deletion abrogated tumor suppression. These findings identify a non-canonical, IL-4–imprinted macrophage program that enables antigen presentation and cooperative T cell immunity in this tumor context. Overall design: The BMDM macrophages of WT or Smyd5 KO were treated with IL-4 for 24 hours and then ATAC library construction was performed