Macrophages are Metabolically Heterogeneous within the Tumor Microenvironment

Macrophages are often prominently present in the tumor microenvironment, where distinct macrophage populations can differentially affect tumor progression. Although the metabolism of macrophages influences their function, little is known about the metabolic characteristics of tumor-associated macrophage (TAM) subsets. Using transcriptomic and metabolomic analyses, we now reveal that pro-inflammatory MHC-IIhi TAMs display a hampered TCA cycle, while reparative MHC-IIlo TAMs show a higher oxidative and glycolytic metabolism. Both TAM populations preferred lactate over glucose as a carbon source to fuel the TCA cycle. However, while lactate supported the oxidative metabolism in MHC-IIlo TAMs, it decreased the metabolic activity of MHC-IIhi TAMs. Lactate subtly affected the transcriptome of MHC-IIlo TAMs, increased L-arginine metabolism and enhanced T-cell suppressive capacity of these TAMs. Overall, our data uncover the metabolic intricacies of distinct TAM subsets and identify lactate as an important carbon source, and metabolic and functional regulator of TAMs.