Interplay between lactate and lactylation in the TME. (IMAGE)

China Anti-Cancer Association

Interplay between lactate and lactylation in the TME.

Caption

Interplay between lactate and lactylation in the TME. Lactylation: In the tumor microenvironment (TME), lactate is produced through the “Warburg effect”. AARS1 acts as a lactate sensor that mediates global lysine lactylation in tumor cells. This enzyme binds lactate and catalyzes the conversion of lactate to lactate-AMP in the presence of ATP, and subsequently transfers lactate to the lysine acceptor residue. The p300 enzyme is a histone acetyltransferase that catalyzes the transfer of an acetyl group from acetyl-CoA to lysine residues on histones, thus resulting in histone acetylation, and is considered a “writer” of histone lactylation. Acidic environment: Acidification of the TME decreases integrin binding to the ECM and E-cadherin expression, and activates proteinases such as MMP-9, cathepsin B, and hyaluronidase-2, thus facilitating tumor cell invasion. Lactate also binds GPR81, thereby influencing cAMP and Ca2+ levels. Metabolic reprogramming: As a key metabolite linking glycolysis and oxidative phosphorylation, lactate is notably involved in energy supply and metabolic regulation in tumor cells. Immune evasion: Lactate also modulates M2 tumor-associated macrophages and leads to remodeling of the immunosuppressive tumor microenvironment through the PI3K/Akt pathway, promotes tumorigenesis by altering MOESIN lactylation, and enhances TGF-β signaling in Tregs. Antitumor immunity: Lactate enhances CD8+ T-cell stemness and regulates Foxp3-dependent RNA splicing via CTLA-4, thereby maintaining Treg phenotype and function. Akt, protein kinase; AARS1, alanyl-tRNA synthetase 1; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; cAMP, cyclic adenosine monophosphate; ECM, extracellular matrix; GPR81, G protein-coupled receptor 81; MMP-9, matrix metalloproteinase 9; PI3K, phosphatidylinositol 3-kinase; TGF-β, transforming growth factor-β; Tregs, regulatory T cells.

Credit

Cancer Biology & Medicine

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