Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells

Regulatory T (Treg) cells play a vital role in maintaining the immunosuppressive tumor microenvironment. Lactate is a crucial metabolite in cancer and is related to tumor prognosis, metastasis, and overall survival. In this study, we focus on the effects of lactate on Treg cells. In vitro, lactate improves Treg cell stability and function, whereas lactate degradation reduces Treg cell induction, increases antitumor immunity, and decreases tumor growth in mice. Mechanistically, lactate modulates Treg cell generation through lactylation of Lys72 in MOESIN, which improves MOESIN interaction with transforming growth factor β (TGF-β) receptor I and downstream SMAD3 signaling. Cotreatment with anti-PD-1 and a lactate dehydrogenase inhibitor has a stronger antitumor effect than anti-PD-1 alone. Individuals with hepatocellular carcinoma who responded to anti-PD-1 treatment have lower levels of MOESIN lactylation in Treg cells than nonresponding individuals. Thus, we identify lactate as an essential small molecule that reinforces Treg cells in the tumor microenvironment through lactylation. [Display omitted] •Lactate increases expression of FOXP3 and enhances Treg cell function•Lactate regulates Treg cells through lactylation of MOESIN at the Lys72 residue•Lactylation of MOESIN at Lys72 enhances TGF-β signaling in Treg cells via TGF-βRI•Individuals responding to anti-PD-1 treatment have lower levels of MOESIN lactylation Lactate is a crucial metabolite in cancer and is related to tumor prognosis, metastasis, and overall survival. Gu et al. find that lactate regulates Treg cells through lactylation of MOESIN at the Lys72 residue, which enhances TGF-β signaling in the tumor microenvironment.