Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis

Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) play critical roles in tumorigenesis. However, the mechanisms underlying MDSC and TAM development and function remain unclear. In this study, we find that myeloid-specific activation of Notch/RBP-J signaling downregulates lactate transporter MCT2 transcription via its downstream molecule Hes1, leading to reduced intracellular lactate levels, blunted granulocytic MDSC (G-MDSC) differentiation, and enhanced TAM maturation. We identify c-Jun as a novel intracellular sensor of lactate in myeloid cells using liquid-chromatography-mass spectrometry (LC-MS) followed by CRISPR-Cas9-mediated gene disruption. Meanwhile, lactate interacts with c-Jun to protect from FBW7 ubiquitin-ligase-mediated degradation. Activation of Notch signaling and blockade of lactate import repress tumor progression by remodeling myeloid development. Consistently, the relationship between the Notch-MCT2/lactate-c-Jun axis in myeloid cells and tumorigenesis is also confirmed in clinical lung cancer biopsies. Taken together, our current study shows that lactate metabolism regulated by activated Notch signaling might participate in MDSC differentiation and TAM maturation. [Display omitted] •Notch signaling represses MCT2-mediated lactate transport in myeloid cells•Lactate promotes M-MDSC differentiation into G-MDSCs rather than mature macrophages•Lactate interacts with intracellular c-Jun to protect from FBW7-mediated degradation•Combining Notch activation and MCT2 inhibition in myeloid cells represses tumor growth Zhao et al. show that Notch-signaling-mediated lactate metabolism in tumor-associated myeloid cells blunts G-MDSC differentiation and enhances TAM maturation. Lactate interacts with intracellular c-Jun to protect from its degradation, leading to COX2 expression. Notch-MCT2/lactate-c-Jun axis in myeloid cells should be targets for tumor therapy.