Research progress of abnormal lactate metabolism and lactate modification in immunotherapy of hepatocellular carcinoma

Abstract

Tumors meet their energy, biosynthesis, and redox demands through metabolic reprogramming. This metabolic abnormality results in elevated levels of metabolites, particularly lactate, in the tumor microenvironment. Immune cell reprogramming and cellular plasticity mediated by lactate and lactylation increase immunosuppression in the tumor microenvironment and are emerging as key factors in regulating tumor development, metastasis, and the effectiveness of immunotherapies such as immune checkpoint inhibitors. Reprogramming of glucose metabolism and the "Warburg effect" in hepatocellular carcinoma (HCC) lead to the massive production and accumulation of lactate, so lactate modification in tumor tissue is likely to be abnormal as well. This article reviews the immune regulation of abnormal lactate metabolism and lactate modification in hepatocellular carcinoma and the therapeutic strategy of targeting lactate-immunotherapy, which will help to better guide the medication and treatment of patients with hepatocellular carcinoma.

Keywords: hepatocellular carcinoma; immune regulation; immunotherapy; lactate metabolism; lactylation.

Figure 1

Lactate is produced by a variety of pathways. Lactates are mainly produced by the aerobic glycolysis pathway and the glutamine pathway. Glucose metabolism reprogramming in HCC promotes glucose uptake by the glucose transporter GLUT1/2. HK2, GAPDH, PKM2 and LDHA are upregulated under the regulation of a variety of cytokines to accelerate lactate production. Glutamine is transported into mitochondria, where it produces α-ketoglutaric acid under the action of GDH, followed by participation in the TCA cycle to produce malate, and finally transported out of the mitochondria to produce lactate.

Figure 2

PPI network of interactions between lactate metabolism-related genes.

Figure 3

Histone lysine lactylation site and the production of lactylation. (A) Histone lysine lactylation site. (B) Lactate metabolism can induce epigenetic remodeling through histone lactylation. After lactate produces lactyl-CoA, the lactosyl group is transferred by p300 to the lysine tail of the histone protein, forming a lactylation modification. Lactyl glutathione (LGSH) hydrolyzed to produce lactate, which forms lactylation modifications through non-enzymatic reactions. HDAC1-3 is a potential delactinase. It is unclear which enzymes produce lactyl-CoA and which enzymes recognize histone lactylation.

Figure 4

Lactate promotes the production of an immunosuppressive microenvironment. The tumor microenvironment is mainly composed of tumor cells, anti-tumor immune cells, tumor-promoting immune cells, blood vessels and cytokines. Lactate acts as an immunosuppressive factor that hinders cytotoxic action in T cells and NK cells while supporting the immunosuppressive function of TAMs, MDSCs and Tregs to promote tumor immune evasion. Lactate also promotes hypoxia and angiogenesis that aggravates the immunosuppressive nature of TME.

Figure 5

Lactate mediates the expression of PD-1 and PD-L1. PD-1 and PD-L1 are mainly activated by a cascade of specific cytokines and related signaling pathways. Lactate regulates PD-1 and PD-L1 expression through TGF-β/SMAD, IL-6/STAT3, HGF/MET signaling pathways, and cytokines and proteins such as IFN-γ, TNF-α, HIF-1α, and GPR81.

Figure 6

Anti-lactate therapy combined with ICIs. Single immune checkpoint inhibitors are less effective in treatment, while simultaneous targeting of glycolysis, lactate production, and transport are more effective.