Lactate-Lactylation Hands between Metabolic Reprogramming and Immunosuppression

Abstract

Immune evasion and metabolic reprogramming are two fundamental hallmarks of cancer. Interestingly, lactate closely links them together. However, lactate has long been recognized as a metabolic waste product. Lactate and the acidification of the tumor microenvironment (TME) promote key carcinogenesis processes, including angiogenesis, invasion, metastasis, and immune escape. Notably, histone lysine lactylation (Kla) was identified as a novel post-modification (PTM), providing a new perspective on the mechanism by which lactate functions and providing a promising and potential therapy for tumors target. Further studies have confirmed that protein lactylation is essential for lactate to function; it involves important life activities such as glycolysis-related cell functions and macrophage polarization. This review systematically elucidates the role of lactate as an immunosuppressive molecule from the aspects of lactate metabolism and the effects of histone lysine or non-histone lactylation on immune cells; it provides new ideas for further understanding protein lactylation in elucidating lactate regulation of cell metabolism and immune function. We explored the possibility of targeting potential targets in lactate metabolism for cancer treatment. Finally, it is promising to propose a combined strategy inhibiting the glycolytic pathway and immunotherapy.

Keywords: immune evasion; immunotherapy; lactate; lactylation; metabolic reprogramming.

Figure 1

Regulation of lactate metabolism progress in normal and cancer cells. Glucose metabolism mainly contains glycolysis and the TCA cycle in the mitochondrion. With sufficient oxygen, normal cells produce energy mainly through the TCA cycle. Under hypoxic conditions, large amounts of lactate are produced. Glycolysis tumor cells produce large amounts of lactate, which transport into TME through the MCT4. Then, lactate can be transported into oxidative tumor cells based on MCT1 as fuel and produce energy by OXPHOS. Abbreviation: ATP, adenosine triphosphate; TCA cycle, tricarboxylic acid cycle; TME, tumor microenvironment; MCT1, monocarboxylate transporter 1; MCT4, monocarboxylate transporter 4; OXPHOS, oxidative phosphorylation, GLUT1, glucose transporter type 1.

Figure 2

Lactate-lactylation forms an inhibitory regulatory network on the immune system in the TME. In the TME, tumor cells consume most nutrients and secrete excessive lactate, resulting in acidosis, angiogenesis, and immunosuppression. Lactate also modulates the metabolism of innate and adaptive immune cells by inhibiting the functions of CD8+ T cells, natural killer (NK) cells, natural killer T (NKT) cells, dendritic cells, and macrophages. By contrast, lactate favors regulatory T (Treg) cells and Myeloid-Derived Myeloid Suppressor Cells (MDSCs), sustaining their immunosuppressive functions in the acidic environment. Summarily, lactate plays a pro-oncogenic role in TME. Abbreviation: ILC2s, group 2 innate lymphoid cells; CTL, cytotoxic T lymphocytes, MCT1, monocarboxylate transporter 1; MCT4, monocarboxylate transporter 4.

Figure 3

Lactate acts as a signaling molecule to affect gene transcription and immune evasion via histones and non-histone lysine lactylation. Lactate promotes lactylation and acetylation of HMGB1 and its release from macrophages via exosomes; it induces vascular endothelial cell injury by decreasing the steady state and promoting vascular permeability. Lactation of lysine at position K72 of MOESIN protein improves the interaction of MOESIN with TGF-β receptor I and downstream SMAD3 signaling and regulates the generation of Treg cells; lactate promotes the transcription of METTL3 in TIMs in the form of histone H3K18 lactate modification. Moreover, lactylation can directly occur in METTL3 protein, which enhances METTL3 binding and catalyzes m6A modification of target RNA; it enhances the expression of downstream immunosuppressive effector molecules IL-6, IL-10, and iNOS. Histone lactylation in macrophages promotes a shift to the immunosuppressive M2 macrophage phenotype. Histone lactylation promotes tumorigenesis by facilitating the transcription of YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2), which recognizes the m6A modification site in the mRNA of two tumor suppressor genes, PER1, and TP53; it promotes their degradation in ocular melanoma; Lactylation of PDGFRB in the histone H3K18 is essential in the oncogenic process. Abbreviation: Kla, histone lysine lactylation; MCT1, monocarboxylate transporter 1; GLUT1, glucose transporter type 1; Ac, Acetylation; METTL3,methyltransferase-like 3; TCA cycle, tricarboxylic acid cycle; YTHDF2,YTH N6-methyladenosine RNA-binding protein 2; PER1, period1; CCRCC, Clear Cell Renal Cell Carcinoma; LDH, lactate dehydrogenase; TGF1B, TGF-β receptor I; STAT3,transcription 3; FOXP3, forkhead box protein p3; JAK1, Janus kinase 1; HMGB1, high mobility group protein B1.

Figure 4

Strategies to target lactate biogenesis and acidosis to enhance immunotherapy response. Combined immunotherapy with drugs targeting lactate production and lactate transporter can enhance the therapeutic effect of immune checkpoint inhibitors.