Histone lactylation as a driver of metabolic reprogramming and immune evasion

Formation of histone lactylation

Histones are composed of repeating units called nucleosomes, each consisting of a core octamer, a monomeric histone, and approximately 200 base pairs of DNA. About 146 base pairs of DNA are wound around the core octamer, with approximately 55 base pairs linking the monomeric histone. Histone modifications, including methylation, acetylation, phosphorylation, and ubiquitination, involve attaching various acyl groups to histone amino acid residues, affecting the tightness of histone-DNA binding. According to the study by Zhang et al. the occurrence of histone lactylation is similar to histone acetylation [1]. When exogenous or endogenous lactate accumulates to a certain concentration, cellular lactylation-regulating molecules are activated. Relevant enzymes use lactyl-coenzyme A as a substrate to transfer lactate to histone residues. This process alters the tightness of histone-DNA binding, indirectly affecting mRNA transcription and protein translation. Lactate can move between cells through “lactate shuttles” involving MCT1 and MCT4, serving as a universal energy source. In tumor cells, even with sufficient oxygen, cells prioritize glycolysis over oxidative phosphorylation for rapid energy acquisition, leading to increased intracellular and extracellular lactate concentrations. High lactate concentrations can induce histone lactylation, regulating DNA damage repair and tumor chemotherapy resistance and impacting immune cell cytotoxicity [2]. This metabolic epigenetic modification links the high-lactate tumor microenvironment created by metabolic reprogramming to tumor immune evasion and resistance to immunotherapy (Figure 1).

Figure 1:

The molecular mechanism of histone lactylation modification formation. The warburg effect promotes glycolysis in tumor cells, leading to the production and accumulation of lactate. The accumulated lactate facilitates the generation of lactyl-CoA, which serves as a donor of lactyl groups for histone lactylation catalyzed by writers. Histone lactylation promotes chromatin opening, with modifications at H3K18 and H3K9 sites found to be closely associated with immune evasion.

Histone lactylation modifications and cancer immune evasion

Histone lactylation in macrophages

The high-lactate environment of the tumor microenvironment induces histone lactylation in macrophages (Figure 2). Studies indicate that histone lactylation mediates the transformation of M1 macrophages, with immune-promoting and tumoricidal functions, into M2 macrophages, which are immunosuppressive and promote tissue repair and tumor progression. Under conditions such as hypoxia, interferon (IFN)-γ, lipopolysaccharide (LPS), or bacterial infection, macrophage lactate levels rise. Accumulated lactate increases histone lysine lactylation modifications at gene promoters, directly regulating gene expression. For instance, histone lactylation enrichment at the promoters of M2-like genes ARG1 and KLF4 increases their expression, shifting macrophages from M1 to M2 phenotype [1]. In colon cancer, lactate in tumor-infiltrating myeloid cells promotes METTL3 expression through H3K18 lactylation and lactylates the zinc finger domain of METTL3. This enhances Jak1 mRNA methylation, binding with YTHDF1 to increase translation efficiency, activating the JAK1-STAT3 signaling pathway and initiating downstream immunosuppressive molecule expression [6]. In glioblastoma, endoplasmic reticulum stress-induced PERK drives glucose metabolism, promoting IL10 expression in monocyte-derived macrophages (MDMs) through histone lactylation, exerting immunosuppressive effects [7]. In PTEN/p53-deficient prostate cancer, reduced lactate production after treatment with PI3K inhibitors reverses TAM histone lactylation-mediated inhibition, stimulating TAM phagocytosis and achieving long-term tumor control with manageable toxicity under intermittent dosing [8].

Figure 2:

Histone lactylation modification promotes cancer immune evasion. The warburg effect promotes tumor production and secretion of lactate, which enhances histone lactylation in cells within the tumor microenvironment. This ultimately leads to the expression of PD-L1 in tumor cells, the production of TGFβ and IL-10 by CD8+ T cells, the expression of CCR8, CD39, CD73, and FOXP3 by CD4+ T cells, and the production of IL-10, IL-6, and iNOS by macrophages, along with the consumption of arginine. These changes collectively contribute to tumor immune evasion.

Discussion

Lactate, as a core energy metabolism substrate, serves as a key intercellular metabolic molecule in the tumor microenvironment. Tumor cells undergoing metabolic reprogramming acquire large amounts of energy via aerobic glycolysis and transport lactate through “lactate shuttles” to other cells in the microenvironment. The significantly increased lactate concentration in tumor microenvironments not only creates a tumor-promoting acidic environment but also provides substrates for lactylation in tumor-associated cells. Research shows that lactate accumulation-induced lactylation directly affects immune checkpoint expression and activates immunosuppressive pathways in immune cells, reshaping the microenvironment. In conclusion, lactate and lactylation modifications play critical roles in tumor immune evasion and resistance to immunotherapy. Targeting lactate metabolism and lactylation modifications represents a promising therapeutic direction, warranting exploration to inhibit the tumor-promoting effects of lactate while preventing lactylation-induced suppression of immune cytotoxicity. In the future, vaccines targeting histone lactylation may be developed, especially circular RNA vaccines, which have the potential to treat histone lactylation related cancers [12]. Investigating these aspects is crucial for advancing cancer treatment strategies.