How tumor cells communicate with tumor-associated macrophages (TAMs) to influence their function is not known. In Nature, Colegio et al. report that tumor-cell production of lactic acid via glycolysis pathways acts on TAMs to upregulate their expression of genes encoding the the growth factor VEGF and the arginase Arg1. Inhibition of monocarboxylate transporters, which blocks the uptake of lactate acid, prevents macrophage expression of Vegf. Lactic acid somehow stabilizes the transcription factor HIF-1α, which then positively regulates the expression of a subset of genes of M2-polarized macrophages. Notably, this response is independent of interleukin 4 (IL-4) or IL-13, cytokines commonly associated with the M2 polarization of macrophages. Macrophage-specific conditional deletion of Hif1a or Arg1 in a tumor model leads to a diminished tumor burden. Thus, bidirectional communication is established between tumor cells and TAMs that is beneficial for tumor growth.

Nature (13 July 2014) doi:10.1038/nature13490