Role of lactylation in tumorigenesis: Analysis based on the ten hallmarks of cancer

Figure 1 Lactylation in the tumor microenvironment is influenced by elevated lactate concentrations, resulting from high sugar fermentation, low oxygen levels, and inflammatory responses. This metabolic environment affects key enzymes such as the lactate dehydrogenase complex, adenosine triphosphate/adenosine diphosphate, and nicotinamide adenine dinucleotide (oxidized form)/nicotinamide adenine dinucleotide (reduced form), which regulate the lactylation of substrate proteins. Acyltransferase complexes, including p300/CBP, catalyze the lactylation of both histone proteins and non-histone proteins, such as transcription factors and metabolic enzymes. These modifications contribute to tumor cell survival, immune regulation, and energy induction through proteins like sirtuin 1/2, histone deacetylase 3, and general control nonderepressible 5. ATP: Adenosine triphosphate; ADP: Adenosine diphosphate; NAD⁺: Nicotinamide adenine dinucleotide (oxidized form); NADH: Nicotinamide adenine dinucleotide (reduced form); SIRT: Sirtuin; HDAC3: Histone deacetylase 3; GCN5: General control nonderepressible 5; H3K23: Histone H3 lysine 23; H3K14: Histone H3 lysine 14.

Figure 2 Lactylation, as a post-translational modification, affects multiple cellular processes by modifying lysine residues on target proteins. This modification enhances cell signaling pathways, such as the nuclear factor kappa-light-chain-enhancer of activated B cells and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathways, promoting cell proliferation and inhibiting apoptosis. It also regulates the cell cycle by modifying key proteins involved in cycle progression. In addition to signaling, lactylation alters chromatin structure, making it more open, and enhances gene expression by activating transcription factors and related genes. The modification also influences protein stability by extending the half-life of proteins, enhances enzyme activity, and induces conformational changes that adjust protein functions. Furthermore, lactylation plays a critical role in metabolic reprogramming and overall protein function enhancement, thereby contributing to tumor progression and immune escape. MMP9: Matrix metallopeptidase 9; LDH: Lactate dehydrogenase; STAT6: Signal transducer and activator of transcription 6; PPAR: Peroxisome proliferator-activated receptor; Arg1: Arginase 1; Mrc1: Mannose receptor C-type 1; TAM: Tumor-associated macrophage; NF-κB: Nuclear factor kappa B; AP-1: Activator protein 1; MMPS: Matrix metallopeptidases; IL: Interleukin; TGF: Transforming growth factor; NK: Natural killer.

Figure 3 Lactylation in the tumor microenvironment modulates immune and matrix remodeling functions. Elevated lactate levels, catalyzed by lactate dehydrogenase, lead to modifications of transcription factors like signal transducer and activator of transcription 6 and peroxisome proliferator-activated receptor-gamma in tumor-associated macrophages, promoting M2 polarization and the expression of immune-suppressive genes such as interleukin-10 and transforming growth factor-β. This modification inhibits the activity of effector T cells and natural killer cells, enhancing the immunosuppressive environment. Additionally, lactylation of fibroblast cell factors like nuclear factor kappa B cells and activating protein-1 promotes matrix remodeling, increasing cell migration, invasion, and metastasis, thus driving tumor progression through immune evasion and enhanced matrix degradation. NF-κB: Nuclear factor kappa B; PI3K/AKT/mTOR: Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin; H3K: Histone H3 lysine; HK2: Hexokinase 2.