Glucose metabolic reprogramming has a vital function in tumor immunity and inflammation. Macrophages are essential components of the innate immune system and play a crucial role in the inflammatory response. Glucose metabolic reprogramming can alter the phenotype of macrophages, hence modulating inflammation (15).

Under inflammatory conditions, M1 macrophages undergo significant glucose metabolic reprogramming to sustain their proinflammatory activities. This process involves the upregulation of glucose transporter 1 (GLUT1) and key glycolytic enzymes including hexokinase 2 (HK2), phosphofructokinase (PFK), and lactate dehydrogenase A (LDHA), which are primarily mediated by NF-κB and STAT3 signaling pathways. A representative study by Xu et al. (16) demonstrated that IL-6 modulates glucose metabolism through formation of a molecular complex comprising STAT3, HK2, and voltage-dependent anion channel 1 (VDAC1), ultimately promoting glycolytic and lactate generation. This metabolic shift further sustains the production of proinflammatory cytokines including TNF-α and IL-6, which is a process essential for both antimicrobial defense and tumor immune surveillance. As inflammation progresses, certain immune cells undergo dynamic metabolic adaptations, with some macrophages transitioning from the M1 to M2 phenotype (17), shifting their metabolic profile toward pathways that support tissue repair processes.

M2 macrophages have reduced glycolysis and preferential use of oxidative phosphorylation. The metabolic profile is characterized by reduced levels of GLUT1 and LDHA, alongside heightened activity of enzymes associated with the tricarboxylic acid (TCA) cycle and mitochondrial respiration. Lactate generated by adjacent tumor cells or fibroblasts is absorbed by M2 macrophages through MCT1, which activates NF-κB signaling and enhances the expression of anti-inflammatory genes such as Arg1 and IL-10. This metabolic reprogramming facilitates tissue repair and enables tumor immune evasion. M2 macrophages suppress T cell activation and promote angiogenesis through PPAR-γ signaling pathways. The differing glycolytic activity of M1 and M2 macrophages highlights their distinct functions in tumor immunity. M1 cells facilitate proinflammatory tumor rejection, while M2 cells create an immunosuppressive environment that supports tumor growth. Blocking glycolytic reprogramming typically leads to the transformation of M1 macrophages into M2 macrophages, thereby facilitating the development of tumor-associated macrophages that exhibit immunosuppression and contribute to tumor immune evasion. In the initial phase of inflammation, the activation of the immune system leads to the activation of T cells, which undergo glycolytic reprogramming. This process involves a transition from mitochondrial oxidative phosphorylation to glycolysis for energy production. Such a shift enables T cells to efficiently support rapid proliferation, differentiation, and the secretion of cytokines, thereby enhancing their role in the immune response and pathogen elimination (18). The primary metabolism of T cells is characterized by low-rate catabolism, generating ATP via pyruvate and fatty acid oxidation. Upon activation, T cell metabolism undergoes reprogramming to support cell growth and clonal expansion, primarily generating ATP through glycolysis and supplying raw materials for biosynthesis. Previous studies indicate that T cell-specific knockout of the Slc2a1 gene, which encodes GLUT1, diminishes glucose uptake and glycolysis, subsequently impairing the proliferation and differentiation of CD4 + T cells (16).

TME refers to the internal conditions that facilitate the development, proliferation, and metastasis of tumor cells. The composition primarily includes tumor cells, adjacent immune cells, cancer-associated fibroblasts (CAFs), a limited extracellular matrix, and cytokines (17). CAFs are located in proximity to tumors, exhibit unique genetic characteristics, and can affect tumor initiation, invasion, and progression through the secretion of cytokines, chemokines, and angiogenic factors. CAFs, similar to tumor cells, experience metabolic reprogramming, shifting to a more glycolytic phenotype and producing metabolic byproducts such as lactate, pyruvate, and ketone bodies, which supply energy to adjacent tumor cells. Metabolic reprogramming is associated with the acidification of the tumor microenvironment, a fundamental characteristic of tumor growth (19).

TME is defined by a multifaceted and dynamic metamorphosis that influences both the biological functions of tumor cells and their responses, and is closely linked to the onset, progression, metastasis, and therapeutic responses of malignancies. Cancer cells exhibiting abnormal metabolism use excessive oxygen and nutrients, leading to hypoxia and an accumulation of metabolic byproducts in the tumor microenvironment. Lactate produced from tumors can polarize tumor-associated macrophages (TAMs) into an anti-inflammatory and immunosuppressive state, hence enhancing tumor survival and growth. Conversely, macrophage polarization can induce metabolic changes inside macrophages (20). Increased metabolites in the tumor microenvironment, especially lactate, provide an immunosuppressive environment that enhances cancer cell proliferation and facilitates immune evasion (21). Lactate serves as an essential signaling molecule as well as an energy substrate. Lactate dehydrogenase (LDH) levels serve as a diagnostic for unfavorable prognosis and the effectiveness of immunotherapy, while serum lactate concentration correlates positively with tumor burden (22). Lactate, a mediator, stimulates the production of pro-inflammatory cytokines, including IL-23 and IL-17, in immune cells that infiltrate tumors, hence enhancing carcinogenesis and diminishing anti-tumor activity. Lactate is essential in establishing an immunosuppressive milieu that facilitates tumor cell proliferation and inhibits the functionality of immune cells as signaling molecules inside TME. It also inhibits immune cell activation by obstructing their glycolytic reprogramming (23).

Lactylation modification is a significant element in macrophage polarization. Research indicates that (31) lactate accumulates in macrophages when they polarize into the M1 phenotype, with a significant increase in histone lactylation during the later phases of this polarization. Histone Kla can modulate the expression of cell-repair genes, such as Arg1, to polarize pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages, thereby affecting the trajectory and outcome of the inflammatory response and promoting the resolution of inflammation after inflammatory or anti-inflammatory activation (9).

Moreover, alterations in lactylation can affect T cell metabolic reprogramming, rendering them more inclined towards glycolytic metabolism and so impacting immunological functions. Regulatory T cells (Tregs), a subset of T lymphocytes characterized by the expression of the transcription factor FOXP3, are essential for immunological tolerance, homeostasis, and tumor immune evasion (32). The quantity of lactate-modified Treg cells within TME increases, along with their functionalities. They can inhibit the function of tumor-specific effector T cells, enabling tumor cells to evade the immune system. A recent study (33) indicates that the tumor metabolite lactate can modulate the lactylation of the MOESIN protein at the Lys72 residue in Treg cells. This enhances the connection between MOESIN and the TGF-I receptor I, as well as downstream Smad3 signaling, hence augmenting the functions of Treg cells and facilitating immunosuppression in the tumor microenvironment.

Besides the aforementioned pathophysiological implications, lactylation’s regulatory function in cancer has garnered significant attention. Moreover, lactic acid will influence the functionality of NK cells, thereby hindering the release of IFN-as Research on mechanisms indicates that excessive consumption of pathological levels of lactic acid by NK cells can lead to intracellular acidification and impede the up-regulation of the nuclear factor of activated T cells (NFAT) signaling pathway, thereby diminishing the production of NFAT-regulated IFN– and facilitating apoptosis (34). Significantly, both human and rat melanoma exhibit elevated levels of lactate. In immune-competent mice, diminishing lactic acid generation can impede tumorigenesis, while the infiltration of CD8+ T cells and NK cells secreting IFN-e within the tumor is markedly enhanced. In mice devoid of lymphocytes and NK cells, the tumorigenic potential exhibited minimal variation between the low lactate group and the control group (35). Recent study has revealed that lactate generated by the glycolysis of tumor cells within TME stimulates the mTOR pathway, resulting in the phosphorylation of the transcription factor TFEB and impeding its nuclear translocation. This alteration transforms tumor-associated macrophages (TAMs) within TME into immune cells that facilitate tumor proliferation. A negative connection between intratumoral lactate levels and overall survival in cervical cancer patients has been documented. Collectively, these data suggest that elevated lactate levels in the tumor and the resultant acidified TME will inhibit immune cell activity and undermine immunological monitoring of cancer, ultimately facilitating immune evasion (36). The elevated lactate levels in the internal environment can diminish the antigen-presenting capacity of dendritic cells (DC) and impair the anti-tumor immune response.

Tumors generate substantial lactate through the Warburg effect and glutamine hydrolysis, thereby activating the monocarboxylate transporters (MCTs) on the cell membrane. Tumor cells can rapidly extrude intracellular lactate to avert excessive intracellular acidification (37). This transport mechanism generates a “inverse pH gradient” between the intracellular and extracellular environments, resulting in an increase in internal pH and a decrease in external pH. This significantly elevates the acidity of TME, impacting immune cell function (38). TAMs, MSCDs, and Tregs in TME are all immunosuppressive. They facilitate tumor proliferation by suppressing anti-tumor immune responses and evading immune surveillance (39) (40). Preserving intracellular redox balance with an appropriate concentration of lactate protects tumor cells from oxidative stress, hence promoting their survival and proliferation. Lactylation can regulate the extracellular matrix. Cancer cells release metabolic byproducts, including lactate, which activate certain signaling pathways such as the PI3K/Akt pathway (41), to regulate cytoskeletal reorganization, the synthesis of cell adhesion molecules, and the function of matrix metalloproteinases. This facilitates the infiltration of cancer cells through the basement membrane, allowing them to infect adjacent tissues and metastasize to distant sites (42).

Lactate strongly influences the proliferation, metabolism, invasion, metastasis, and angiogenesis of tumor cells. Generally, tumor cells generate substantial quantities of lactic acid owing to their elevated glycolytic rate, which functions as an essential energy source for their survival and proliferation. Tumors utilize lactate in two distinct manners to generate energy (43). Lactate is utilized by cancer cells to interact with fibroblasts (CAFs). CAFs utilize lactate produced by aerobic glycolysis to facilitate the proliferation and dissemination of adjacent cancer cells. Secondly, the Warburg effect induces hypoxic cellular populations inside TME to generate substantial quantities of lactate. MCTs transport lactate to adjacent cells for oxidative phosphorylation (44). Lactate additionally has endocrine-like, paracrine, and autocrine activities inside the tumor microenvironment. Besides supplying sufficient energy for cancer via energy redistribution and effective use through the lactate shuttle mechanism, it also facilitates cancer invasion and metastasis by enhancing cell-to-cell interactions through the autocrine-paracrine signaling loop (45). Lactate can accelerate the development and metabolism of cancer cells by regulating key enzymes (46), including PDK-1 and LDH. LDHA and LDHB are the two subunits of the lactate dehydrogenase (LDH) enzyme group, which facilitate the reversible transformation of pyruvate into lactate. Essentially, LDHB oxidizes lactate to pyruvate, while LDHA preferentially reduces pyruvate to lactate and regenerates NAD+. Dysregulation of LDH levels, characterized by the overexpression of LDHA and the downregulation of LDHB, often promotes tumor proliferation (47). LDHA is a prospective target for oncological treatment, especially for malignancies reliant on the Warburg effect. Lactate activates HIF and c-Myc, leading to the expression of these two enzymes in cancer cells, enhancing aerobic glycolysis and ensuring sufficient energy for growth and proliferation in hypoxic conditions. Lactate promotes tumor development and invasion by inhibiting the degradation of HIF-1d and stimulating the synthesis of vascular endothelial growth factor (VEGF).

Lactate and lactylation collaborate to circumvent anti-tumor immunity. Extracellular lactate decreases pH, hindering CD8+ T cell migration and NK cell cytotoxicity, whereas intracellular lactyl-CoA, produced from lactate, facilitates the lactylation of essential proteins. Lactate-induced lactylation of MOESIN at Lys72 in Tregs fortifies its association with TGF-c receptor I, hence augmenting Smad3 signaling and Treg suppressive efficacy. Tumor cells export lactate through MCT4, which is absorbed by macrophages, leading to H3K18 lactylation and M2 polarization, so establishing a pro-tumor feedback loop (96, 97).

Glycolysis is the principal pathway that generates lactate. Glucose is converted into pyruvate via a series of metabolic reactions under anaerobic or hypoxic conditions. LDH facilitates the conversion of pyruvate into lactate (48). A novel post-translational modification in the body is histone lactylation. Histone lactylation can be promoted by the external administration of sodium lactate and by increased endogenous lactate concentrations. Consequently, two significant factors affecting lactylation are lactate production and transport. The balance between glycolysis and mitochondrial metabolism is the principal factor influencing lactate production. The synthesis of lactate and, subsequently, the extent of lactylation in this process can be significantly influenced by alterations in the activity of key enzymes in the glycolytic pathway. Glycolysis accelerates, resulting in increased lactate production and enhanced lactylation, particularly when the activity of hexokinase, phosphofructokinase-1, and pyruvate kinase rise in response to heightened cellular energy demands. Lactate transport is another significant component affecting lactylation. MCTs are crucial in the lactate transport route (49). MCT4 predominantly transports intracellular lactate out of the cell, while MCT1 principally facilitates the influx of extracellular lactate into the cell. The dynamic equilibrium of lactate within and outside the cell is ensured by their existence. Under standard physiological conditions, MCT1 transports lactate into the cell as extracellular lactate concentrations increase, hence augmenting the availability of lactate for lactylation within the cell. Elevated MCT4 expression in tumor cells facilitates the retention of intracellular lactate, promotes the efflux of substantial quantities of endogenously produced lactate, and indirectly affects lactylation modification (50). The correct production and localization of MCT1 and MCT4 on the cell membrane can be facilitated by CD147, a co-chaperone protein of MCTs (51). The maintenance of sufficient lactate transport is significantly reliant on this synergistic effect. Aberrant CD147 expression will affect the activities of MCTs, modifying intracellular lactate content and transport efficiency, hence influencing the extent of lactylation (52, 53).

Histone acetyltransferases (HATs), which catalyze the transfer of lactyl-CoA, are the primary “writer enzymes” involved in the enzymatic process of lactylation. Since they are extremely similar proteins, CBP (CREB-binding protein) and p300 (E1A-associated 300 kDa protein) are frequently referred to as CBP/p300. For numerous transcription factors, CBP/p300 acts as a co-activator. According to research, CBP/p300 can function as a “writer enzyme” during the enzymatic process of lactylation of proteins (48). Under specific circumstances, they can transfer the lactyl group on lactyl-CoA to the lysine residues of proteins utilizing their catalytic domains, resulting in lactylation modification of proteins (54). The degree of lactylation can be significantly impacted by changes in the expression level of CBP/p300 (55). Kla rises in human embryonic kidney 293T cells (HEK293T) when p300 is overexpressed. This suggests that the lactylation reaction can be facilitated and the amount of lactylation raised by up-regulating the expression of CBP/p300 (56, 57). On the other hand, histone lactylation is reduced in human colon carcinoma 116 (HCT116) cells and HEK293T cells when p300 is knocked down (58).

Histone deacetylases 1-3 (HDAC1-3) are referred to as “eraser enzymes” (59) because they can remove lactate groups from proteins and have delactylating action. It is possible to alter the lactylation status of proteins by controlling the actions of these enzymes. They alter the chromatin state and control gene expression by removing the lactylation modification on histones during the regulation of gene expression in cells (60). For instance, HDAC1–3 may be activated to eliminate the lactylation modification on histones, compacting the chromatin structure and inhibiting gene expression when cells need to lower gene transcription activity.

Notably, CBP/p300 and HDAC1–3 exhibit opposing roles in tumor immunity (61) (62). In ovarian cancer, CBP/p300 overexpression correlates with enhanced H3K18 lactylation and aggressive glycolysis, while HDAC1 downregulation in colorectal cancer promotes Treg cell-mediated immunosuppression via sustained histone lactylation (63). This reciprocal regulation highlights their potential as therapeutic targets for rebalancing tumor metabolism and immunity. Beyond ovarian and colorectal cancers (64), CBP/p300 and HDAC1–3 exhibit context-dependent roles in multiple malignancies. In breast cancer (65), CBP/p300-driven lactylation of FOXP3 enhances Treg suppressive function via TGF-β/Smad3 signaling, while HDAC1 downregulation correlates with M2 macrophage infiltration (66). In hepatocellular carcinoma, CBP/p300 cooperates with HIF-1αto lactylate HK2 and VEGF, promoting glycolysis and angiogenesis, whereas HDAC1 activation restores lactate efflux balance to sensitize tumors to immunotherapy.

Notably, in NSCLC (67), HDAC3 loss sustains H3K18 lactylation at the PD-L1 promoter, driving immune checkpoint upregulation (68). These findings highlight the dual roles of lactylation regulators as both metabolic sensors and epigenetic drivers, with implications for precision oncology. For example, the CBP/p300 inhibitor CPI-0610 shows promise in preclinical models of pancreatic cancer by disrupting the lactylation-TTK/BUB1B feedback loop, while HDAC1 agonist entinostat reverses immunosuppression in colorectal cancer by de-repressing CD8+ T cell infiltration.

Controversies persist regarding lactylation specificity. Although most lactylation events rely on lactate as a substrate, recent studies identify lactate-independent pathways, such as the generation of lactyl-CoA from non-glycolytic sources like amino acid metabolism. Additionally, lysine residues modified by lactylation (e.g., H3K18) can compete with acetylation for stoichiometric occupancy. In macrophages, acidic TME conditions favor lactylation over acetylation at shared sites, potentially reprogramming gene expression toward immunosuppression. These findings highlight lactylation as a context-sensitive modification with nuanced regulatory mechanisms.

Activation of signaling pathway is the core driving force of lactate modification by regulating lactate metabolism and modifying enzyme activity. It has been found that the regulation of lactate level involves several pivotal signaling pathways, such as HIF-1α pathway, mTOR pathway and PI3K/Akt signaling pathway. The hypoxia-inducing factor HIF-1α is activated under hypoxia, and the expression of glycolytic related genes (LDHA, GLUT1, etc.) is up-regulated, which promotes the production of lactic acid. Previous studies have shown that HIF-1α can also influence intracellular lactate levels by regulating the activity of lactate transporters (such as MCT1), indirectly driving histone lactate modification. When the mTOR (69)pathway is activated, the body promotes glycolysis and inhibits oxidative phosphorylation, which aggravates lactic acid accumulation. Some scholars have found that mTORC1 may directly participate in the process of lactation by regulating the activity of lactate modification enzymes (such as lactate transferase). Glycolysis, lactate generation, and lactylation modification can all be enhanced by activation of the PI3K/Akt pathway, which can also boost the expression and translocation of glucose transporters and the cell’s absorption of glucose (70). The distribution of lactate and the lactylation process can also be further controlled by the PI3K/Akt pathway, which can further control the expression and function of lactate transporters.

Recent advances reveal intricate crosstalk between HIF-1α, mTOR, and PI3K/Akt pathways in regulating lactylation, which is profoundly shaped by tumor microenvironmental contexts. HIF-1α acts as a central hub, not only enhancing glycolysis and lactate production but also upregulating MCT1 to boost intracellular lactyl-CoA availability for lactylation (71). Under hypoxia, HIF-1α suppresses mTORC1 to redirect metabolism toward glycolysis, while in normoxic regions, mTORC1 phosphorylates CBP/p300 at Ser1834 to enhance its lactyltransferase activity, preferentially modifying non-histone proteins like FOXP3 in Tregs (72).

The PI3K/Akt pathway reinforces this network by phosphorylating HK2 and HIF-1α, simultaneously promoting glycolysis and lactylation while inhibiting HDAC3-mediated delactylation. For example, in colorectal cancer, PI3K/Akt-driven β-catenin lactylation at K49 enhances its interaction with TCF/LEF transcription factors, upregulating MCT4 and PD-L1 to form a pro-tumorigenic feedback loop (73). These findings highlight a ‘context-switching’ mechanism where HIF-1α and mTOR/PI3K/Akt pathways dominate in hypoxic vs. normoxic niches, respectively, to fine-tune lactylation for tumor adaptation and immune evasion.