Lactate and lactylation in tumor immunity

Abstract

The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate’s role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate’s importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.

Keywords

lactate / lactylation / tumor immunity / TME / immunosuppressive immune cells

1 Introduction

Nearly a century ago, Otto Warburg proposed the phenomenon of the Warburg effect based on in vitro experiments demonstrating that tumor cells produce lactate even under aerobic conditions, highlighting their preference for glycolysis over oxidative phosphorylation (OXPHOS) for metabolic transformation [1]. Tumor cells preferentially adopt glycolysis, a less energy-efficient metabolic mode than OXPHOS, not only for its rapid ATP production but also for generating intermediate metabolites essential for biosynthesis [2,3]. Notably, a similar metabolic reprogramming to glycolysis occurs in activated immune cells, enabling them to meet the energy demands of rapid proliferation and functional activation [4]. However, within the TME, nutrient competition between tumor and immune cells limits glucose availability to immune cells, resulting in impaired function. Additionally, lactate, a well-established immunosuppressive molecule, plays a critical role in reshaping immune cell function. These combined factors ultimately suppress anti-tumor immunity, facilitate immune escape, and promote tumor progression and metastasis [4].

The TME exhibits a highly dynamic and evolving nature. During tumor progression, tumor cells release cytokines and chemokines to recruit immune cells, while immune cells further secrete chemokines to attract additional immune cell populations into the TME [5]. When tumor clearance fails, lactate accumulates both intracellularly and extracellularly. Acting as a signaling molecule, lactate binds to membrane receptors or is transported into immune cells to reshape their function through multiple signaling pathways. Infiltrating immune cells gradually undergo phenotypic changes, transitioning from normal to immunosuppressive phenotype that promotes tumor growth under the influence of the TME [5]. The acidic, metabolically dysregulated, and immunosuppressive microenvironment poses significant challenges for effective tumor treatment. Consequently, therapies combining targeted lactate metabolism and immune checkpoint inhibitors have become a cornerstone of cancer treatment, offering novel options for patients resistant to conventional anti-tumor drugs [6].

2 Lactate binds to its receptor

Lactate, also referred to as “lactormone,” serves as a pivotal, multifunctional signaling molecule within the TME, exerting autocrine, paracrine, and endocrine-like effects that modulate immune cell functions and communications through binding to its specific receptors [7]. The signaling pathway of lactate and its receptor is implicated in various stages of tumor development, promoting tumor growth independently of monocarboxylate transporters (MCTs). In the following text and table, we summarize the signaling pathways involving lactate-related receptors GPR81, GPR132, and MAVS, as well as their roles in tumorigenesis and progression (Table 1).

2.1 Lactate/GPR81 signaling axis

G protein-coupled receptor 81 (GPR81), also known as the hydroxycarboxylic acid receptors (HCARs), is a member of the GPCR subfamily, with lactate serving as its natural ligand [8]. GPR81 expression has been observed in key tissues such as the kidney, heart, and skeletal muscle, among others [9,10]. In various tumor cells, GPR81 expression is elevated and correlates with increased rates of tumor cell proliferation and metastasis. GPR81 is essential for tumor cell survival, and its silencing reduces lactate transporter expression, downregulates companion proteins, and decreases mitochondrial activity, ultimately leading to cell death [8]. Lactate-induced induction of MCTs via the GPR81 signaling pathway is critical for efficient lactate transport and metabolism [11]. In the TME, lactate acts on GPR81 expressed on tumor cells through autocrine signaling or on GPR81 expressed on non-cancer cells, such as immune cells, to promote tumor growth and metastasis [8].

In tumor cells, GPR81 is upregulated in breast cancer and improves the redox status of mitochondria, promoting tumor cell proliferation through the lactate-GPR81/IGFBP6 axis [12]. In estrogen receptor-positive (ER⁺) breast cancer, tamoxifen-resistant tumor cells express lower levels of GPR81, leading to disruption of the Rap1 pathway, upregulation of peroxisome proliferator-activated receptor α (PPARα) and carnitine o-palmitoyltransferase 1 (CPT1), which enhances fatty acid oxidation (FAO) and inhibits autophagy, ultimately promoting the growth of tamoxifen-resistant tumor cells [13]. Furthermore, lactate has been shown to activate GPR81 expression in lung cancer cells via the Snail/EZH2/STAT3 signaling pathway, inducing upregulation of programmed death ligand 1 (PD-L1). Through the cAMP/TAZ/TEAD-dependent signaling pathway, this contributes to tumor cell evasion of cytotoxic T cell-mediated killing [14,15]. In esophageal cancer (EC), the BCT protein of Fusobacterium periodonticum induces lactate accumulation and promotes epithelial-mesenchymal transition (EMT) in EC109 cells via the GPR81/Wnt/β-catenin signaling pathway, which may be a key mechanism underlying EC pathogenesis [16]. In uveal melanoma (UM), sustained exposure to IL-6 results in the production of lactate, which binds to GPR81, inhibiting the ubiquitination and degradation of PD-L1 and human leukocyte antigen-E (HLA-E), thereby enhancing tumor cell resistance to cytotoxic T cell- and NK cell-mediated killing [17]. Additionally, the lactate/GPR81 signaling pathway has been implicated in cancer cachexia, a complication associated with malignant cancers [18]. Metformin, a promising cancer treatment, has been shown to significantly enhance its anti-tumor effects by blocking both the lactate/GPR81 and PD-1/PD-L1 signaling pathways [19]. For immune cells, in myeloid cells, lactate binds to GPR81 on myeloid-derived suppressor cells (MDSCs), activating the GPR81/mTOR/HIF-1α/STAT3 pathway to induce immunosuppressive responses in pancreatic cancer [20]. Studies have also indicated that peroxisome proliferative-activated receptor (PPAR)-mediated signaling may regulate GPR81 expression in intestinal antigen-presenting cells (APCs), ultimately suppressing inflammation and restoring intestinal homeostasis [21,22]. Lactate downregulates the NLRP3 inflammasome induced by Toll-like receptors (TLRs) and inhibits inflammatory factor production in macrophages and monocytes via ARRB2 and GPR81. Additionally, lactate inhibits type I interferon (IFN) induction in plasmacytoid dendritic cells (pDCs) through GPR81 binding, mediated by intracellular Ca²⁺ mobilization [23,24]. Lactate binding to GPR81 on DCs also impairs antigen presentation of tumor-specific antigens to other immune cells [25]. In lymphocytes, lactate at high concentrations in the gastric cancer (GC) TME binds to GPR81, inducing the expression of the chemokine CX3CL1, which recruits regulatory T cells (Tregs), ultimately fostering immune tolerance and the progression of GC [26].

In summary, regardless of whether lactate in the TME acts on GPR81 receptors of tumor cells or immune cells, it induces an immunosuppressive microenvironment, promoting tumor cell proliferation, invasion, and metastasis. However, no research has yet indicated whether the lactate/GPR81 pathway exerts a synergistic pro-tumor effect through both tumor cells and immune cells. Further investigation is needed to determine whether the lactate/GPR81 receptor pathway plays a pro-tumor role in all high-lactate TMEs and its contribution to immune suppression within the TME. Additionally, it is unclear whether this pathway acts in concert with other signaling pathways to exert its pro-tumor effects. More extensive research is required to provide conclusive evidence.

2.2 Lactate/GPR132 signaling axis

GPR132, also known as G2A, is a member of the pH-sensing GPCR family, although its pH-sensing ability is weaker than that of other family members. It is highly expressed in lymphoid tissues and macrophages, playing a vital role in regulating both innate and adaptive immunity [27,28]. Research has demonstrated that GPR132 indirectly promotes M1-like macrophage phenotypes via positioning macrophages in an inflammatory microenvironment during acute inflammation [29]. However, in the TME, GPR132 in macrophages has been identified as a pro-tumor factor. The lactate/GPR132 pathway facilitates the M2 phenotype of tumor-associated macrophages (TAMs), which accelerates tumor cell invasion and growth [30,31]. In addition, studies have indicated that Olfr78, an odor receptor, can form a heterodimer with Gpr132, enhancing its expression and promoting the M2 phenotype of TAMs, thereby driving tumor progression and metastasis [32]. In ovarian cancer, GPR132 has proven to be a significant receptor on macrophages, where lactate binding increases macrophage infiltration and polarization toward M2 phenotype. This also significantly inhibits CD8⁺ T cell function, an effect attributed to MYC oncogene-mediated inhibition of HIF-1α degradation. This immunosuppressive effect can be mitigated by targeting Gpr132, underscoring the significance of the lactate/GPR132 signaling pathway in MYC-mediated ovarian cancer [30,33]. In colorectal cancer, upregulation of the platelet reactive protein 2 (THBS2) promotes M2 polarization of TAMs and inhibits T cell proliferation and cytotoxicity through the HIF-1α/lactate/GPR132 pathway, thereby suppressing anti-tumor immunity [34]. Other studies have shown that GPR132 is dispensable for normal T and B cell development, and it plays a vital role in maintaining peripheral lymphocyte numbers to ensure homeostasis by regulating the threshold of T cell receptor (TCR)-dependent activation and proliferation. Mice lacking GPR132 develop a late-onset autoimmune syndrome [35]. Additionally, GPR132 has been proposed as a therapeutic target for tumors. In acute myeloid leukemia (AML), the second-generation imipridone ONC212, a novel anti-tumor drug, induces apoptosis by targeting high GPR132-expressing AML cells [36]. Currently, there are limited data on whether targeting GPR132 in other tumor types can similarly eliminate tumor cells and reverse the immunosuppressive microenvironment.

2.3 Lactate/MAVS axis

MAVS (mitochondrial antiviral signaling protein) is a mitochondrial surface protein and a mitochondrial localization protein that is essential for retinoic acid-inducible gene-I-like receptor (RLR) signaling [37]. As a direct lactate sensor, MAVS can disrupt its own mitochondrial localization, prevent the interaction between RIG-I and MAVS, and hinder MAVS aggregation, thereby limiting RLR signaling activation and type-I IFN production, which are crucial for host defense against viral infections and tumor immunosurveillance [38]. Investigation has revealed that lactate binding to MAVS inhibits HBV-induced aggregation and mitochondrial localization, promoting immune evasion by HBV [39]. During senecavirus A (SVA) infection, glycolysis and lactate production are enhanced in PK-15 cells and mice, accelerating SVA replication by attenuating RIG-I/MAVS interactions and inhibiting the production of type-I IFN [40]. Recent studies have found that, SVA infection upregulates migration inhibitory factor (MIF) expression, which, through HIF-1α, increases lactate production, inhibiting the RIG-I signaling pathway and promoting SVA replication [41]. In bladder cancer (BC), methionine metabolism increases YTHDF1 expression, which inhibits the RIG-I/MAVS-mediated IFN-I pathway and enhances PD-L1 expression via the YTHDF1/eIF5B axis, thereby reducing tumor immunotherapy efficacy and promoting cancer progression [42]. The inhibition of the RIG-I/MAVS pathway has also been observed in non-small cell lung cancer (NSCLC) and high-grade serous ovarian cancer, where it exerts an immunosuppressive effect and promotes tumor growth [43,44]. This suppression of RIG-I/MAVS-mediated anti-tumor immunity in the TME has spurred research into activating the RIG-I/MAVS pathway to enhance anti-tumor immunity. Small molecule Ro 90-7501, DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors (DNMT/HDACi) 15a, and ataxia telangiectasia mutated (ATM) inhibitors have been shown to activate the RIG-I/MAVS pathway and enhance anti-tumor immunity in colon, breast, and pancreatic cancers, respectively [45–47]. Relevant clinical trials have shown that MK-4621, an oligonucleotide that binds and activates RIG-I, exhibits moderate anti-tumor activity in patients with advanced solid tumors [48].

3 Lactate shuttle

Given its pivotal role in tumor progression, lactate not only participates in tumor immune regulation through specific receptor signaling pathways, but also serves as a key mediator of cellular crosstalk within the TME. This dual function is further reinforced by its dynamic exchange within the TME, where lactate shuttle mechanisms critically influence cellular interactions and metabolic adaptation.

Oncogenes and mutated tumor suppressor genes reprogram glycolysis to promote lactate production by creating a concentration gradient that facilitates lactate exchange between and within cells. This lactate exchange is primarily driven by concentration, pH, and redox status [7]. Lactate can be utilized not only by tumor cells but also by other cell types, particularly immune cells [49]. It can traverse the cell membrane through three mechanisms: free diffusion, ion exchange, and transporter-mediated transport, with the latter being the most crucial [50]. The main MCTs facilitate the transport of single-carboxylates (e.g., lactate) along with protons, thereby eliminating lactate from tumor cells into the TME, significantly influencing the TME’s pH [51]. As local tissue microenvironments change, regulatory mechanisms within the body can modulate MCT protein activity and expression to control lactate distribution across various tissues [52]. Among the identified MCTs, MCT1-4 play a key role in maintaining lactate homeostasis under physiologic conditions, facilitating bidirectional transport of monocarboxylates [53,54]. Notably, MCT1 and MCT4 are critical for lactate transport in the TME. MCT1 exhibits a high affinity for lactate, with its expression regulated by lactate levels, enabling the influx of lactate to support tumor cell growth [55–57]. MCT4, primarily expressed in highly glycolytic cells, is induced by hypoxia-inducible factor 1α (HIF-1α) and is responsible for exporting lactate into the extracellular microenvironment, which stimulates cytokine production. Elevated MCT4 expression is considered a marker of poor prognosis in multiple tumors [58–62]. In summary, due to the rapid growth of tumors outpacing blood vessel formation, hypoxic tumor cells distant from blood vessels export lactate, catalyzed by lactate dehydrogenase A (LDH-A), into the TME via MCT4. In contrast, normoxic tumor cells near blood vessels oxidize lactate to synthesize ATP, catalyzed by LDH-B and mediated by MCT1, facilitating glucose diffusion to oxygen-deprived tumor cells, which supports the survival of hypoxic cells [63] (Fig. 1). Lactate shuttling is essential for its physiologic functions [7]. Moreover, in the TME, MCT1 and MCT4 exhibit differential expression across various immune cell subsets and play distinct roles in lactate transport, thereby influencing the fate and function of immune cells. Lactate, excreted by tumor cells at high concentrations, not only inhibits lactate efflux from immune cells but also can be transported into nearby immune cells, such as macrophages, through transporters like MCT1. Inside these cells, lactate is converted back into lactyl-CoA, which then serves as a substrate for histone acetyltransferases, such as p300, to catalyze histone lactylation, reshaping their functions and promoting an immunosuppressive phenotype. Ultimately, lactate released by tumor cell metabolism acts on various immune cells to reshape their function, promoting an immunosuppressive TME, leading to tumor immune evasion (Fig. 2).

4 Lactate reshapes tumor-infiltrating immune cells

4.1 Lactate inhibits cytotoxic T lymphocytes (CTLs)

The reduced infiltration of CTLs and cytokine secretion in tumor tissues is closely associated with the immunosuppressive microenvironment induced by lactate. In terms of cytokine production, a high extracellular level of lactate in TME can be internalized by CTLs, competitively hindering the release of endogenous lactate. The resulting decrease in pH within CTLs can interfere with the nuclear translocation of nuclear factor of activated T cells (NFAT), a crucial transcription factor regulating interferon-γ (IFN-γ) transcription. IFN-γ has been shown to promote the reprogramming of myeloid-derived suppressor cells (MDSCs), which are abundant in tumors, into antigen-presenting cells [64]. Lactate can also downregulate the phosphorylation of MAPKs p38 and JNK/c-Jun, key downstream signaling molecules involved in TCR activation and essential for cytokine gene transcription, thereby suppressing CTL cytokine production [65]. Additionally, lactate can reprogram CTL pyruvate metabolism, preventing activation of succinate receptor 1 (SUCNR1), a pro-inflammatory G protein-coupled receptor that induces cytotoxic molecules for tumor cell elimination [66]. Regarding CTL infiltration within the TME, lactate inhibits their motility, hindering their recruitment in sufficient numbers [67]. Furthermore, lactate-induced macrophage polarization can upregulate PD-L1 expression, which promotes CTL apoptosis and aids tumor immune evasion [68]. Ultimately, lactate diminishes both the cytotoxic activity and proliferation of CTLs [69].

4.2 Lactate supports the enrichment of regulatory T cells (Tregs)

Tregs are essential for the maintenance of immune homeostasis and are abundant in the TME, where they represent a dominant cell population. First, Tregs exert potent inhibitory effects on effector T cells (Teffs) in the TME, thereby dampening anti-tumor immunity and facilitating recruitment of a substantial number of Tregs by tumor cells [70]. Lactate-induced HIF-1 increases the expression of triggering receptor expressed on myeloid cells-1 (TREM-1) in TAMs, which subsequently recruits Tregs to mediate immunosuppression via the extracellular signal-regulated kinase/nuclear factor κB (NF-κB) pathway [71]. The balance between Teffs and Tregs in tumor immunity significantly impacts tumor treatment and prognosis [72]. Secondly, the low-glucose, high-lactate environment of the TME impairs Teff and cytotoxic T lymphocyte (CTL) function, weakening their ability to kill tumor cells. Meanwhile, metabolic reprogramming of Tregs, mediated by Myc transcription and Foxp3-driven enhancement of glycolysis, oxidative phosphorylation, and nicotinamide adenine dinucleotide (NAD) oxidation, gives Tregs a metabolic advantage in the TME, promoting peripheral immune tolerance and aiding in immune evasion by tumor cells [73]. Foxp3, as a transcriptional regulator, is essential for the development and suppressive function of Tregs. Lactate promotes the expression of Foxp3 by regulating RNA splicing [74]. Furthermore, lactate serves as a gluconeogenic fuel for Tregs, reducing their glucose demand while generating phosphoenolpyruvate (PEP), which is essential for Treg proliferation and accumulation in the TME [75]. Lastly, lactate-induced phenotypic transformation also contributes to the accumulation of Tregs in tumor tissues through modulation of other immune cell populations. (1) Lactate generated during inflammation can inhibit pro-inflammatory Th17 cell-driven inflammation and induce Th17 reprogramming into Tregs by downregulating IL-17A and upregulating Foxp3 [76]. (2) Lactate enhances tryptophan metabolism and promotes kynurenine production in plasmacytoid dendritic cells (pDCs), thereby inducing Foxp3⁺ Tregs [23]. (3) Lactate helps tumor cells evade immune surveillance by reducing the CD4⁺ Th1 population and promoting the polarization of CD4⁺ naïve T cells into pro-tumoral Tregs mediated by Foxp3 [77]. Additionally, high lactate levels in the TME induce PD-1 expression in Tregs and upregulate inhibitory markers such as CD25 and cytotoxic T lymphocyte antigen 4 (CTLA-4) via intranuclear NFAT signaling [72].

4.3 Lactate promotes apoptosis of naïve T cell

Lactate in naïve T cells downregulates nicotinamide adenine dinucleotide (NAD) levels, which translationally inhibits the expression of FAK family-interacting protein of 200 kDa (FIP200). FIP200 deficiency enhances the degradation of argonaute 2 (Ago2), impairing the formation and maturation of the Ago2-microRNA 1198-5p complex. This disruption affects the balance between the apoptotic gene Bak1, which is suppressed by microRNA 1198-5p, and anti-apoptotic Bcl-2 family members, ultimately promoting apoptosis in naïve T cells [78].

4.4 Lactate blunts immunosurveillance of natural killer (NK) cells

NK cells play an indispensable role in immune surveillance, effectively inhibiting tumor growth and metastasis [79]. However, within the TME, NK cell effector functions can be compromised due to metabolic competition for glucose between NK cells and tumor cells [80]. Lactate further reduces NK cell activity by decreasing the expression of critical cytotoxic molecules such as perforin and granzyme B, while specifically inhibiting natural cytotoxic receptors [81]. For instance, lactate can modulate immune response genes like natural cytotoxicity triggering receptor 1 (NCR1), which encodes activating receptors on NK cells, acting as an endogenous inhibitor of histone deacetylases [82]. Additionally, the development of myeloid-derived suppressor cells (MDSCs) impairs NK cell cytotoxicity by reducing perforin and granzyme B expression and hindering mTOR signaling and the nuclear localization of downstream PLZF [81,83]. Lactate also inhibits cytokine production in NK cells by suppressing the upregulation of NFAT, a factor increased during T cell activation, particularly affecting the production of IFN-γ. This cytokine is essential for activating NK cells and suppressing tumor growth through inhibition of angiogenesis and direct tumor cell proliferation. Consequently, lactate promotes tumor immune evasion and growth [64]. In colorectal liver metastasis, lactate reduces the intracellular pH value of liver-resident NK cells, leading to mitochondrial dysfunction and inducing ROS-mediated cell apoptosis [84].

4.5 Lactate promotes polarization of tumor-associated macrophages (TAMs)

Monocytes, the precursors of TAMs, can be inhibited from migrating and releasing cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) by lactate [85]. Tumor-derived lactate serves as an energy source for monocytes, which uptake lactate via MCT1, thereby promoting the synthesis of prostaglandin E2 (PGE2) and gluconeogenesis to supply glucose to tumor cells, accelerating tumor growth [86]. Macrophages generally exhibit two distinct phenotypes: M1, which primarily functions in pathogen elimination, and M2, which adopts an anti-inflammatory phenotype to facilitate wound healing [87,88]. During the early stages of tumor development, TAMs exhibit proinflammatory and antitumor activity. However, as the tumor progresses, TAMs polarize toward the M2 phenotype under the influence of lactate [89,90]. This polarization is characterized by increased expressing of M2-associated genes such as Arg1, Vegf, and Mgl1 and a reduction in the expression of M1-associated genes such as iNOS, CCL2, and IL-6. This shift is mediated by pseudo-hypoxic activation of HIF proteins or the activation of the extracellular signal-regulated kinase (ERK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, and is accompanied by increased lactate utilization [49,91,92]. Furthermore, lactate-induced activation of the mammalian target of rapamycin complex 1 (mTORC1) suppresses the macrophage-specific vacuolar ATPase subunit ATP6V0d2 expression via TFEB, leading to the lysosomal degradation of HIF-2α in macrophages. The sustained presence of HIF-2α enhances tumor vascularization and growth [93]. Research has also shown that lactate facilitates M2 polarization through the mTORC2 and ERK signaling pathways, promoting pituitary adenoma (PA) invasion via the CCL17/CCR4/mTORC1 axis [94].

4.6 Lactate suppresses dendritic cell (DC) presentation antigen

DCs are pivotal antigen-presenting cells that recognize, capture, and present tumor-associated antigens to T cells [95]. Peripheral DCs exhibit low levels of MHC II and costimulatory molecules on the cell surface when immature, but display elevated levels of MHC II and costimulatory molecules after maturation to facilitate T cell activation and effector differentiation [96]. Tumor-infiltrating DCs in cancer patients have been shown to be both phenotypically and functionally defective, with lactate playing a key role in this process. In tumors, lactate, either alone or in combination with cytokines, can modulate the antigen expression of DCs, leading to the generation of tumor-specific DCs. Furthermore, lactate significantly impairs the antigen presentation capacity, migration, and monocyte-to-DC differentiation of these cells [97]. Specifically, lactate strongly inhibits the differentiation of IL-12-producing CD1a⁺ DCs [98].

4.7 Lactate promotes N2 phenotype of neutrophils

Exogenous lactate can induce the formation of neutrophil extracellular traps (NETs) in human neutrophils, a process that plays a pivotal role in both innate immune defense and the pathophysiology of various inflammatory diseases [99]. Similar to macrophages, neutrophils within the TME display phenotypic polarization into N1 and N2 subsets, with N1 neutrophils exhibiting antitumor activity (ROS, TNF-α) and N2 neutrophils promoting tumor progression (ARG1, CCL2, IL-10). While both N2 neutrophils and M2 macrophages contribute to immune suppression and metastasis, they originate from different lineages and respond to distinct polarizing signals, highlighting complementary yet non-redundant roles in tumor immunity [100]. Tumor-derived lactate upregulates PD-L1 expression on neutrophils, promoting their polarization into the N2 phenotype through the MCT1/NF-κB/COX-2 signaling pathway. This process prolongs neutrophil lifespan, ultimately leading to the suppression of anti-tumor immunity [101].

5 Lactate promotes posttranslational modifications of proteins

The integrity and stability of the genome are closely linked to epigenetic modifications. However, in tumorigenesis, genomic stability is compromised, and abnormal histone post-translational modifications become more prevalent [102]. To date, various histone modifications such as acetylation, methylation, phosphorylation, and ubiquitination have been well-documented. In 2019, Zhang et al. introduced lactylation, a novel epigenetic modification mediated by lactate, which promotes gene regulation through lactate-induced modification of histone lysine residues [88]. This discovery has deepened our understanding of lactate’s immunosuppressive effects in the TME. Lactate not only inhibits tumor-infiltrating immune cells but also regulates tumor immunity through epigenetic modulation via histone and nonhistone lactylation. Lactate-induced histone lactylation in immune cell promoter regions by adding lactyl groups to lysine residues, affects gene transcriptional activity, thereby directly regulating gene expression and reshaping immune cell function. This modification is mediated by histone acetyltransferases (HATs) such as p300. Additionally, lactylation of nonhistone proteins can influence immune regulation by altering protein structure and function. These changes drive tumor progression, including survival, proliferation, and invasion, through a series of signaling pathways [88]. Recent studies have highlighted the capacity of tumor-associated microbiota to metabolize host-derived metabolites and modulate host immune cell functions through microbial-host metabolic interactions [103]. Certain bacterial species, such as Fusobacterium nucleatum, which are enriched in colorectal tumors, possess the enzymatic machinery capable of activating short-chain carboxylic acids into their CoA derivatives in an ATP-dependent manner [104]. But direct evidence of lactyl-CoA generation by microbiota is currently lacking. These microbially derived metabolites, including potentially lactyl-CoA or its precursors, may be transferred to host immune cells through outer membrane vesicles or via local diffusion and metabolic exchange. Once inside immune cells, lactyl-CoA may serve as a donor for histone lactylation, thereby influencing gene expression patterns associated with immune suppression and tumor progression. Moreover, lactylation exhibits complex interactions with other histone modifications—such as acetylation and methylation—jointly regulating chromatin structure and gene expression. Studies have shown that lactylation can compete with acetylation for the same lysine sites, thereby influencing transcriptional activity [105]. Additionally, lactylation may indirectly regulate the levels and functions of other modifications by affecting the activity of enzymes such as HDACs [106]. The direct regulation of gene expression through lactylation highlights its significance in various mammalian systems. Both intracellular and exogenous lactate influence lactylation levels, and with ongoing research, an increasing number of histone and nonhistone lactylation sites are being identified (Fig. 3).

5.1 The effect of histone lactylation

5.1.1 Histone lactylation and inflammation repairï

Lactate plays a crucial role in wound healing following inflammatory injury by providing energy and maintaining physiologic pH levels that support cell proliferation and differentiation [107]. Further studies have demonstrated that the inflammatory microenvironment promotes lactate entry into immune cells, regulating the expression of repair-related genes through histone lactylation [107]. Macrophages, essential for antigen presentation, new tissue formation, and angiogenesis, are critical for maintaining tissue homeostasis under both normal and damaged conditions [87]. Upon exposure to various stresses, bone marrow-derived macrophages (BMDMs, M0) are activated by pattern recognition receptors (PRRs), such as TLRs, which trigger NF-κB activation, leading to M1 polarization and the production of pro-inflammatory cytokines. In the later phase of M1 polarization, the B cell adapter for PI3K (BCAP) activates the PI3K-AKT pathway, inhibiting inflammatory gene expression while promoting homeostatic gene expression through histone lactylation. Additionally, upregulation of H3K18la-specific genes, such as Arg1, involved in wound healing, is linked to the metabolic characteristics of M1 macrophages that facilitate their transition into reparative M2 macrophages [88,108]. Another study revealed that mitochondrial dynamics, including fission and fusion, are closely related to macrophage functional transformation, with mitochondrial fragmentation promoting histone lactylation, supporting pro-decomposition reactions and phagocytosis after inflammation activation [109]. Emerging evidence also indicates that lactylation of pyruvate kinase M2 (PKM2) inhibits its tetramer-to-dimer conversion, enhancing pyruvate kinase activity and promoting the reparative transition of pro-inflammatory macrophages [110]. Relevant studies have shown that histone lactylation expedites early remote activation of the reparative transcriptional response in monocytes, fostering an anti-inflammatory and pro-angiogenic environment, which significantly improves cardiac function following myocardial infarction [111]. And the accumulation of lactate in macrophages and histone lactylation caused by MCT4 deficiency drives the transformation of macrophages to a repair phenotype and can also improve the development of atherosclerosis [112]. While in metabolic dysfunction-associated steatotic liver disease (MASLD), increased histone lactylation in hepatic macrophages promotes M1 polarization. This occurs through a positive feedback loop involving hexokinase 2 (HK2)/glycolysis/H3K18la, which enhances metabolic stress and inflammatory burden [113] (Table 2).

5.1.2 Histone lactylation and fibrosis

The progression of inflammatory repair, fibrosis, and tumors is a dynamic process. Chronic inflammation leading to irreversible tissue repair can cause excessive fibrosis, creating a mutagenic microenvironment conducive to tumor formation. Furthermore, numerous studies have highlighted the shared characteristics and molecular mechanisms between fibrosis and tumors [114].

In pulmonary fibrosis, the accumulation of the metabolite lactate is closely associated with the progression of fibrosis [115]. Lung myofibroblasts and alveolar macrophages are pivotal in fibrosis, secreting profibrotic cytokines and producing lactate via metabolic reprogramming. This lactate can induce histone lactylation in the promoter regions of fibrosis-related genes, such as ARG1, PDGFA, THBS1, and VEGFA, in macrophages, thereby promoting a fibrotic-friendly phenotype and accelerating the progression of pulmonary fibrosis [116]. In PM_2.5-induced pulmonary fibrosis, alveolar macrophages also undergo metabolic reprogramming to produce lactate, which enhances the expression of pro-fibrotic genes like Tgfb, Vegfa, and Pdgfa by inducing histone lactylation at their promoter regions. The TGF-β/Smad2/3 and VEGFA/ERK signaling pathways, which are associated with epithelial-mesenchymal transition (EMT), play crucial roles in the progression of pulmonary fibrosis [117]. Studies on pulmonary fibrosis induced by arsenite have shown that alveolar epithelial cells can take up extracellular lactate, resulting in increased lactylation of H3K18. This modification facilitates recognition of the m⁶A site on NREP mRNA, upregulating NREP expression by promoting the transcription of the m⁶A reader protein YTHDF1, ultimately activating TGF-β1 secretion and driving the transformation of fibroblasts into myofibroblasts [118] (Table 2).

In hepatic fibrosis, the activation of hepatic stellate cells (HSC) and their transdifferentiation into α-smooth muscle actin (α-SMA)-positive myofibroblasts is a central pathway driving fibrosis progression. The imbalance between extracellular matrix production and degradation further contribute to the development of fibrosis [119]. During liver regeneration, activation of HSCs leads to lactate production through the expression of HK2 via aerobic glycolysis. This lactate production induces histone lactylation at gene promoters, playing a critical role in the sustained activation of HSCs and the progression of liver fibrosis [120]. Additionally, a study demonstrated that insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), an m⁶A binding protein highly expressed in activated HSCs, regulates the expression of Aldolase A (ALDOA), a key enzyme in glycolysis. Through lactate-induced histone lactylation, IGF2BP2 further upregulates genes associated with HSC activation, promoting fibrosis development [121] (Table 2).

5.1.3 Histone lactylation and tumorigenesis

An increasing body of research has shown that histone lactylation is closely linked to immune suppression and tumor progression within the TME. This provides insight into a potential new mechanism by which the acidic TME promotes tumor immune suppression. Lactate no longer functions solely as a metabolic signaling molecule for reshaping tumor-infiltrating immune cells, and it also exerts a significant influence on tumor immunity through epigenetic regulation via histone lactylation (Table 2).

In ocular melanoma, studies have demonstrated that YTHDF2 expression is facilitated by histone lactylation, which recognizes the m⁶A-modified PER1 and TP53 mRNAs, leading to their degradation and accelerating tumorigenesis [122]. Additionally, histone lactylation induces the upregulation of the demethylase ALKBH3, which reduces the methylation of SP100 and inhibits its expression. This dysregulation disrupts promyelocytic leukemia protein (PML) condensation, promoting cancer progression [123]. Another study shows that histone lactylation can upregulate the expression of B7-H3, reduce the proportion and cytotoxicity of tumor-infiltrating CD8⁺ T cells, and promote tumor immune evasion [124].

In studies related to NSCLC, elevated levels of histone lactylation have been shown to enhance tumor immune evasion by activating the pore membrane protein 121 (POM121)/MYC/PD-L1 signaling pathway [125].

In breast cancer, aerobic glycolysis-induced histone lactylation upregulates the oncogenic transcription factor c-Myc, driving alternative splicing of MDM4 and Bcl-x by regulating the expression of serine/arginine splicing factor 10 (SRSF10). This process enhances tumor progression [126]. Histone lactylation also upregulates the expression of USP39. As a splicing factor, USP39 influences the expression and alternative splicing of certain oncogenes or tumor suppressor genes through its splicing function, thereby affecting cell fate, and promotes malignant progression of endometrial cancer (EC) through its interaction with PGK1 and the PI3K/AKT/HIF-1α signaling pathway [127].

In acute myeloid leukemia, STAT5-induced lactate accumulation promotes nuclear translocation of E3BP, increasing histone lactylation on the PD-L1 promoter and enhancing its transcription. This process reduces CD8⁺ T cell activation, ultimately leading to immunosuppression [128].

In glioblastoma (GBM), increased histone lactylation-driven LINC01127 expression promotes GBM cell self-renewal via the MAP4K4/JNK/NF-κB signaling pathway [129]. Furthermore, histone H3K9 lactylation mediates the retention of MLH1 intron 7, reducing MLH1 expression by activating the transcription of LUC7L2, which inhibits mismatch repair and contributes to temozolomide (TMZ) resistance in GBM [130]. Another research shows that acetyl-CoA synthetase 2 (ACSS2) catalyzes lactyl-CoA synthesis and, together with lysine acetyltransferase 2A (KAT2A), forms a lactyltransferase complex that promotes histone lactylation and tumor immune evasion [131]. While in GBM-associated monocyte-derived macrophages (MDMs), high expression of glucose transporters 1 (GLUT1) increases lactate production and histone lactylation, leading to upregulation of IL-10 expression and suppression of T cell activity. The PERK/ATF4 signaling pathway plays a critical role in regulating both GLUT1 expression and histone lactylation in this context [132]. In glioma, guanosine triphosphate succinyl-CoA synthetase (GTPSCS) functions as a nuclear lactyl-CoA synthetase, catalyzing the synthesis of lactyl-CoA. It subsequently cooperates with p300 to promote histone lactylation and GDF15 gene expression, thereby enhancing tumor cell proliferation and radioresistance [133].

In clear cell renal cell carcinoma (ccRCC), inactive von Hippel-Lindau (VHL) associated with metabolic reprogramming induces high levels of lactate lactylation, subsequently stimulating histone lactylation. This activation further triggers transcriptional upregulation of platelet-derived growth factor receptor β (PDGFRβ), establishing a positive feedback loop that fosters tumor cell proliferation and migration, ultimately expediting ccRCC progression [134].

Lactylation of histone H3K18 in gastric cancer (GC) promotes the expression of VCAM1 and promotes the proliferation and metastasis of GC cells via the AKT-mTOR-CXCL1 signaling axis [135]. Histone lactylation also regulates the transcription of TTK and BUB1B, which, in turn, enhance the expression of histone writer protein P300, driving the progression of pancreatic ductal adenocarcinoma (PDAC) [136]. In colorectal cancer (CRC), lactate-induced histone lactylation in CRC tissues, through enriched LPS derived from intestinal bacteria, upregulates the expression of LINC00152 by modifying its promoter. This modification diminishes the binding efficiency of YY1, a transcription factor that negatively regulates LINC00152. As a result, LINC00152 serves as a risk factor for poor prognosis in cancer patients, promoting cell invasion and migration by inhibiting bacteria-induced inflammation [137]. Additionally, GPR37 can promote the lactylation of H3K18la through the Hippo signaling pathway, thereby promoting the expression of CXCL1 and CXCL5, which drive liver metastasis in CRC [138]. In myeloid cells infiltrated by colon cancer, lactate enhances the expression of methyltransferase-like 3 (METTL3), an m⁶A modified protein, through histone lactylation. This synergistically upregulated the expression of Jak1 alongside the m⁶A reading protein YTHDF1, resulting in increased phosphorylation of STAT3 and promoting the expression of immunosuppressive genes within tumor-infiltrating myeloid cell populations (TIM). Moreover, lactylation of METTL3 further enhances m⁶A modification of Jak1 mRNA [139]. In CRC-infiltrated macrophages, histone lactylation suppresses the expression of the RARγ gene and inhibits the tumor necrosis factor receptor-associated factor 6 (TRAF6)/NF-κB signaling pathway. It also enhances the IL-6-STAT3 axis signaling, promoting tumor progression [140]. In CTLs of KRAS mutant CRC, histone lactylation activates circATXN7 transcription, which increases CTL sensitivity to activation-induced cell death. This occurs by masking its nuclear localization signaling motif, which binds to the NF-κB p65 subunit, ultimately leading to immunosuppression and tumor immune escape [141]. Furthermore, in the context of drug resistance to targeted therapy in CRC, increased histone lactylation accelerates the transcription of RUBCNL/Pacer, which interacts with beclin1 to promote autophagosome maturation and recruit the class III phosphatidylinositol 3-kinase complex, contributing to the proliferation and survival of hypoxic cancer cells [142].

5.2 The effect of nonhistone lactylation

5.2.1 Nonhistone lactylation and tumorigenesis

With the continuous publication of research on the correlation between histone lactylation and the progression of various tumors, mechanisms involving nonhistone lactylation in promoting tumorigenesis have also been proposed. As a transcriptional enhancer of VEGFA, HIF1α serves as a pivotal regulator of angiogenesis under hypoxic conditions. Lactylation of HIF1a induced by lactate uptake into prostate cancer (PCa) cells via MCT1 enhances the transcription of KIAA1199, a hyaluronic acid (HA) binding protein also known as cell migration inducing protein/CEMIP. This protein facilitates angiogenesis and vasculogenic mimicry (VM) in PCa through HA-mediated VEGFA signaling [143]. The lactylation of MRE11 after DNA damage in cancer can enhance its DNA binding capacity, thereby inducing homologous recombination process, a DNA repair mechanism that contributes to chemotherapy resistance [144]. In esophageal cancer (EC), hypoxia promotes cell proliferation and invasion by facilitating lactylation of the SHMT2 protein, which then increases its expression and interacts with MTHFD1L [145]. In another interesting research, it is found that high copper content in malignant GC promotes the lactylation of METTL16 and improves the efficacy of cuproptosis induced by the combination of copper ionophore-elesclomol and AGK2 in GC [146]. And elevated vps34 lactylation levels in lung and gastric cancer tissues enhance their kinase activity, increasing their metabolic fitness by removing damaged organelles and proteins, thereby promoting cancer progression [147]. Another study highlights that increased glycolysis in CRC cells stimulates the lactylation of the oncogene β-catenin, enhancing its protein stability and promoting cell proliferation through the Wnt signaling pathway, which regulates cancer stemness [148]. And the serine/glycine-free diet (–SG diet) can suppress CRC growth and enhance antitumor immune responses. Lactylation of PD-L1 represents a mechanism of immune evasion during cytotoxic T cell-mediated antitumor responses. Blocking the PD-1/PD-L1 signaling pathway can restore the recruitment of CD8⁺ T cells induced by the –SG diet. These findings suggest that combining the –SG diet with immunotherapy may improve therapeutic efficacy [149]. Glycolytic-promoted nucleolin (NCL) lactylation allows it to bind to the primary transcript of MAP kinase-activated death domain protein (MADD), upregulating MADD through RNA splicing-dependent mechanisms, which ultimately drives intrahepatic cholangiocarcinoma (iCCA) progression via the MAPK/ERK pathway [150]. Lactylation of NMNAT1 enhances its role in the NAD salvage pathway, promoting the survival of pancreatic adenocarcinoma (PAAD) cells under glucose deprivation [151]. In cervical cancer, lactate-induced lactylation of DCBLD1 stabilizes its expression, and DCBLD1 can upregulate the expression of glucose-6-phosphate dehydrogenase (G6PD) and activate the pentose phosphate pathway (PPP), which promotes the progression of cervical cancer [152]. In tumor-infiltrating immune cells, lactylation of MOESIN at Lys72 enhances TGF-β RI signaling via establishing an additional hydrogen bond between Lys72 and TGF-β RI. This modification helps maintain the tumor immunosuppressive microenvironment by inducing the production of Tregs through the TGF-β-SMAD3-FOXP3 axis [153] (Table 3).

6 The “writer”: lactyltransferases

Lactate serves as a key substrate for post-translational protein modifications. Under conditions of hypoxia or enhanced glycolysis, which lead to elevated intracellular lactate levels, lactate can be converted into lactyl-CoA and subsequently participate in lysine lactylation. The enzymes responsible for lactylation are regulated by lactate metabolism and, in turn, can influence cellular metabolism and gene expression through lactylation modifications. Lactylation of proteins is mediated by writer proteins, known as lactyltransferases, which share similarities with many other posttranslational modifications, such as acetylation. These enzymes catalyze the addition of lactyl groups to histones and other nonhistone lysine residues, thereby regulating gene expression and the function of proteins. Enzymatic lactylation closely mirrors acetylation, as both acetyltransferases and lactyltransferases are capable of directly adding lactyl-CoA to lysine residues [154]. Recent findings highlight that both histone acetylation and lactylation are catalyzed by the same histone acetyltransferase, p300, using acetyl-CoA and lactyl-CoA as respective cofactors. These modifications can occur at overlapping lysine residues such as H3K18 and H3K23, suggesting a potential competition for modification sites and cofactor availability [88,155]. Under high-lactate conditions typical of the TME, increased lactyl-CoA may outcompete acetyl-CoA for p300 binding, thereby reducing histone acetylation and promoting histone lactylation. This shift in epigenetic landscape can selectively activate gene programs associated with anti-inflammatory or M2-like phenotypes in macrophages, while repressing M1-related inflammatory pathways. Furthermore, lactate-induced histone lactylation has been shown to enhance the transcription of M2 signature genes, contributing to an immunosuppressive TME. In contrast, acetylation marks are generally associated with pro-inflammatory M1 polarization [156]. Thus, the balance between lactylation and acetylation may act as an epigenetic rheostat in macrophage polarization. The P300/CREB binding protein (CBP), as a well-known histone acetyltransferase, has been shown to modestly increase histone lactylation when overexpressed in HEK293T cells. In contrast, deletion or inhibition of P300 using C646 significantly reduces histone lactylation [50,88]. In addition, acetyltransferase KAT8 has been identified as another lactylation writer protein. In CRC, the pan-lactylation activity of KAT8, particularly its lactylation of eEF1A2, promotes tumor progression. Conversely, depletion of KAT8 reduces lactylation levels in CRC and inhibits tumorigenesis [157]. HBO1 is another enzyme shown to catalyze histone lactylation and is associated with tumorigenesis [158]. Furthermore, alanyl-tRNA synthetase (AARS1) senses lactate accumulation in tumors, enters the nucleus, and catalyzes the lactylation of the YAP-TEAD complex, promoting tumor cell proliferation through downstream signaling pathways. Elevated AARS1 expression is correlated with poor prognosis [159]. AARS1 can also lactylate p53, facilitating tumor development, while β-alanine disrupts this lactylation, thereby alleviating tumor progression [160]. YiaC has also been shown to regulate the function of prokaryotic Escherichia coli as a lactylation writer protein that catalyzes the lactylation of lysine [161]. And there is evidence supporting a nonenzymatic lactylation process mediated by lactoylglutathione (LGSH), which is hydrolyzed by glyoxalase 2 (GLO2) to generate lactate. This lactate is then transferred to lysine residues in proteins. In macrophages exposed to lipopolysaccharide (LPS), lactoylglutathione (LGSH)-mediated histone lactylation enhances the inflammatory response [162].

7 The “eraser”: histone delactylases

Since lactylation of histone can alter the functionality of immune cells, histone delactylases possess the ability to reverse this functional change. Recent research has confirmed that mammals harbor two families of lysine deacetylases, namely HDAC1–11 and SIRT1–7. Within the HDAC1–11 families, HDAC1‒3 is the main histone deacetylase in cells and collaborates with lactylation enzymes influencing various physiologic and pathological processes through epigenetic regulation lactylation of proteins [163,164]. Among the SIRT1–7 family members, SIRT2 displays superior enzymatic activity and effectively inhibits neuroblastoma cell proliferation and migration, and SIRT3 activation has been demonstrated to eliminate cyclin E2 (CCNE2) lactylation to induce apoptosis of hepatocellular carcinoma (HCC) cells while inhibiting the development of HCC [165,166]. In prokaryotic Escherichia coli, CobB has been shown to erase YIAC-catalyzed lysine lactylation in vivo and in vitro [161].

8 Targeted lactate-related therapy

Lactate suppresses antitumor immune responses through multiple mechanisms. It impairs the effector functions of CD8⁺ T cells and NK cells, reduces the antigen-presenting capacity of DCs, and promotes the polarization of TAMs toward an immunosuppressive M2 phenotype. Collectively, these effects compromise the efficacy of immunotherapies, including immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies. In addition, lactate-induced histone lactylation has been shown to alter gene expression profiles in both immune and tumor cells, thereby facilitating tumor immune evasion. Targeting lactate metabolism or interfering with the lactylation pathway may thus represent promising strategies to enhance the therapeutic efficacy of cancer immunotherapy. Overall, lactate and lactylation levels not only reflect the metabolic status of tumors but also play critical roles in modulating immune escape and treatment sensitivity. In certain tumors, lactate has been recognized as an indicator of high malignancy and unfavorable prognosis [167,168].

LDH is responsible for the production of lactate while MCT mainly plays an effect on lactate transport. LHD1-5 is a tetramer composed of varying numbers of subunits, namely LDHA and LDHB [169]. Among these, LDHA, particularly LHD5 which consists of four LDHA subunits, exists in skeletal muscle and other highly glycolytic tissues, and has a higher Vmax for conversion of pyruvate to lactate. On the other hand, LDHB contributes to gluconeogenesis by oxidizing metabolic lactate or converting it back to pyruvate [169]. Studies have also demonstrated the involvement of LDHA in various processes related to brain tumor formation such as migration and invasion [170]. Furthermore, during chemotherapy for the tumor, increased LDHA expression and activity are associated with resistance to paclitaxel, dexamethasone, and bortezomib [171,172]. Therefore, targeting inhibitors specific to LDHA holds promise as an attractive treatment strategy inhibiting tumor growth and invasion (Table 4).

MCT1-4 is an important mediator of monocarboxylate shuttling between various tissues and cells [173]. Because these MCTs are located on the cell membrane, they can transport substrates bidirectionally depending on the concentration gradient [174]. Lactate produced by glycolysis of hypoxic tumor cells is excreted extracellularly through MCT4, while normoxic tumor cells transport lactate to intracellular oxidative metabolism via MCT1 [173]. Previous studies have shown that the stability of MCT and its localization and functional role requires interaction with CD147, a cell surface chaperone of the multifunctional immunoglobulin family, which is the main chaperone of MCT1, MCT3, and MCT4, and that this interaction is necessary for proper localization of MCT1 and MCT4 to the plasma membrane, and their stability is also interdependent [174,175]. In various tumor types, the overexpression of MCT1 and MCT4 has been extensively documented and is closely related to the progression and worsening prognosis of tumors [176]. Targeting MCT1 inhibitors can impede lactate flux, leading to a metabolic shift from lactate-driven oxidative phosphorylation to aerobic glycolysis in normoxic tumor cells, ultimately resulting in the demise of anoxic tumor cells due to glucose deprivation. In addition, MCT1 inhibitors can interfere with the acquisition of additional lactate from stromal cells by normal-oxygenated tumor cells [174]. Precise inhibition of MCT4 can impair lactate efflux, thus acidifying the cytoplasm of hypoxic tumor cells, inhibiting glycolysis, and inducing their apoptosis [174]. Consequently, continuous research efforts are being devoted to developing drugs that target lactate transporters for effective tumor treatment (Table 4).

Among drugs targeting lactylation, there is also research demonstrating that demethylzeylasteral (DML), a triterpene anti-tumor compound, exhibits inhibitory effects on angiogenesis and tumor cell proliferation in various tumors. Moreover, it has been found to suppress H3 histone lactylation, thereby effectively inhibiting the proliferation and migration of liver cancer stem cells (LCSCs) while promoting apoptosis to inhibit the tumorigenicity of LCSCs [177]. CircXRN2 binds to the SPOP degradation degron, preventing SPOP-mediated LATS1 degradation and thereby inhibiting bladder cancer progression driven by H3K18 lactylation following activation of the Hippo signaling pathway [178]. The Numb/Parkin pathway can promote Parkin-mediated mitochondrial autophagy to clear dysfunctional mitochondria, while its functional deficiency leads to increased histone lactylation and upregulation of neuroendocrine-related genes after metabolic reprogramming in neuroendocrine tumors. Therefore, Numb/Parkin pathway may be a therapeutic target for regulating histone lactylation to control the fate of cancer cells [179] (Table 4).

9 Conclusions

Lactate, once considered a mere byproduct of anaerobic metabolism in muscles, has emerged as a key energy source for various cell types. In addition to glucose, lactate can be utilized by cells such as neurons and cancer cells to produce ATP, the essential energy currency within cells. Beyond its role in energy production, lactate also functions as a signaling mediator, activating specific pathways involved in immune cell activation and inflammation regulation. By binding to receptors on immune cells or being transported into them, lactate can reprogram immune cells into an immunosuppressive phenotype, promoting immune evasion, tumor progression, and metastasis. Furthermore, lactate exerts epigenetic regulatory effects on gene expression through lactylation. It influences both histone and nonhistone lactylation, which can alter gene expression profiles related to cellular metabolism and immune responses, ultimately driving cancer progression.

Although significant progress has been made in understanding lactate and lactylation, many questions remain to be explored. (1) While lactate acts as both a metabolic signaling molecule and an epigenetic regulator of tumor immunity, it remains unclear whether these effects occur simultaneously or if they vary with different lactate concentrations. (2) Although lactate’s role in epigenetic regulation is recognized, several non-specific lactylating enzymes have been identified, highlighting the need for further research into more specific ones. It is also crucial to explore whether lactylation sites undergo other epigenetic modifications and if these modifications might compete with one another. (3) Lactylation occurs not only on histones but also on nonhistone proteins, influencing their stability, structure, and function. However, it is still unknown whether lactylated proteins in the TME exhibit selective preferences that drive tumor progression. (4) There are currently no highly sensitive imaging or molecular tracing tools available to monitor the distribution and dynamics of lactate or lactylation in vivo in real time, which hampers the investigation of their dynamic roles in tumor therapy. (5) Tumor cells, immune cells, and even tumor-associated microorganisms can all produce lactate. However, the transport and functional roles of lactate between different cell types have not been systematically elucidated, making it difficult to identify the source and target of specific lactate signaling. (6) Lactate metabolism is not an isolated process, and it is highly intertwined with glycolysis, lipid metabolism, and the TCA cycle. However, current research rarely integrates lactate and lactylation into the broader context of interconnected metabolic networks for systematic investigation. These questions warrant further investigation.

The advancement of our knowledge about the intricate relationship between lactate metabolism and tumor treatment strategies holds immense promise for improving cancer therapies. Targeting lactate metabolism could disrupt the energy production process within tumor cells, thereby inhibiting their growth and survival. Additionally, modulating histone lactylation levels offers a potential approach to enhance anti-tumor immunity. By altering histone lactylation, we could modulate the expression of genes involved in immune response pathways, improving the body’s ability to recognize and eliminate cancer cells. Moreover, targeted manipulation of lactate metabolism and histone lactylation may sensitize tumors to existing therapies, such as chemotherapy or radiation, leading to improved treatment outcomes. Overall, as our understanding of this field grows, targeted modulation of lactate metabolism and epigenetic regulation offers great promise for revolutionizing cancer therapy, potentially improving patient outcomes and paving the way for more personalized treatments in the future.

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