PTMs involve the covalent addition of chemical groups to amino acid residues, altering protein function. Common PTMs, including phosphorylation, acetylation and ubiquitination regulate chromatin dynamics and gene expression (11). Histones, comprising core (H2A, H2B, H3 and H4) and linker (H1 and H5) subtypes, undergo PTM, and these PTMs are involved in epigenetic regulation (12). Lactylation modification modulates chromatin structure, DNA-histone interactions and transcriptional activity. Hypoxia-induced pyruvate accumulation drives lactylation, particularly at histone 3 lysine 18 (H3K18), H4K5 and H4K18 residues, while H4K5 lactylation (H4K5la) is associated with a poor prognosis in neuroblastoma (13,14). In neuroblastoma studies, elevated lactylation levels of the 5th lysine residue of histone H4 (H4K5la) were found to be notably associated with a poor clinical prognosis in patients (15).

Non-histone lactylation occurs across organelles (nucleus, mitochondria and lysosomes) and regulates several processes, including glycolysis, inflammation and oxidative stress (16–18). By altering protein conformation, charge and stability, lactylation impacts enzyme activity and molecular interactions. For example, in hepatocellular carcinoma (HCC), adenylate kinase 2 lactylation at K28 suppresses mitochondrial function, driving metastasis (19). In lung squamous cell carcinoma, glucose transporter 1-driven lactate accumulation induces lactylation of non-histone proteins [such as N6-adenosine-methyltransferase 70 kDa subunit (METTL3)], thereby enhancing the immunosuppressive tumor microenvironment, reducing the response to immunotherapy and promoting tumor progression (20). Similarly, in pancreatic ductal adenocarcinoma (PDAC), lactylation of the ENSA protein inhibits the phosphatase PP2A, activating the STAT3/CCL2 axis. This axis recruits tumor-associated TAMs and impairs cytotoxic T cell activity (21).

Non-histone protein lysine lactylation (Kla), an emerging PTM, has gained notable attention in oncology research. However, elucidating its mechanisms and achieving clinical translation present substantial challenges. Although enzymes such as p300, alanyl-tRNA synthetase (AARS1) and lysine acetyltransferase 8 (KAT8) have been reported as potential lactyltransferases, most possess acyltransferase activity for acetylation and crotonylation (Kcr). For example, KAT8 catalyzes eukaryotic translation elongation factor 1a2 K408 lactylation to promote protein synthesis in colorectal cancer (CRC). However, its affinity for lactoyl-CoA (Km ≈28 µM) is markedly lower compared with for acetyl-CoA (Km ≈12 µM), raising questions about its preferential catalysis of lactylation under high-lactate conditions (22). Non-enzymatic lactylation mediated by lactoylglutathione has been reported in liver and breast cancer; this type of modification is not enzyme-regulated, making it difficult to target via catalytic enzyme inhibition, and its physiological importance remains unclear. Functional outcomes of lactylation also exhibit tissue-specific discrepancies. For example, p53 K120 lactylation suppresses its tumor-suppressive function in gastric cancer (23) yet stabilizes the protein and enhances DNA repair in glioma (24). Such context-dependent effects underscore that lactylation functions are highly dependent on the microenvironment, suggesting that single mechanistic models can oversimplify the actual complexity.

Lactylation, a dynamic PTM, is regulated by three classes of proteins: Writers (lactyltransferases), erasers (delactylases) and readers (lactylation-recognition factors). Collectively, these components orchestrate lactate modification on histones and non-histone proteins by mediating its addition, removal and functional interpretation, thereby modulating gene expression and cellular physiology (Fig. 1). Writers catalyze the addition of a lactate group to lysine residues: p300, a histone acetyltransferase (HAT) with dual roles in acetylation and lactylation, was first identified as a lactyltransferase by Zhang et al (2), linking it to pathologies including pulmonary fibrosis (25), several types of cancer (26) and Parkinson's disease (27). Lysine acetyltransferase 7 (HBO1), a MYST-family acyltransferase, mediates several histone modifications such as acetylation, Kcr and lactylation (28). HBO1 preferentially targets H3K9la, and elevated H3K9la levels in cervical cancer are strongly associated with HBO1 overexpression (5), driven by its high affinity for lactyl-CoA to regulate oncogenic genes. Erasers remove lactate modifications to reset histone states: Histone deacetylase (HDAC) 1–3 and sirtuin (SIRT) 1–3 function as zinc- and NAD⁺-dependent deacetylases with broad delactylase activity, cleaving both ε-N-L-lactylated and D-lactylated residues (29). SIRT2 specifically removes H3K18la/H4K8la to suppress neuroblastoma proliferation and migration (30), while SIRT3 inhibits HCC by regulating cyclin E2 lactylation levels (31). Readers transduce lactylation signals: SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4 (Brg1), a chromatin remodeler, recognizes H3K18la at promoters of pluripotency genes to facilitate transcriptional reprogramming (32).

Lysine lactylation, as a novel metabolism-dependent PTM, engages in a complex and dynamic interplay with other PTMs. This network orchestrates tumor progression through mechanisms including competitive occupancy of modification sites, shared catalytic enzymes, cascading signaling and epigenetic reprogramming. Kla exhibits substrate competition with lysine acetylation (Kac) and Kcr, a relationship governed by fluctuating metabolite concentrations and shared enzymatic machinery. HATs p300/CREB-binding protein (CBP) and HBO1 possess dual lactyltransferase/acetyltransferase activity and can catalyze multiple acylation types. For example, HBO1 preferentially catalyzes either lactylation (H3K9la) or acetylation (H3K9ac) at histone H3K9, with the type of modification dictated by the intracellular lactate-to-acetyl-CoA ratio (33,34). Similarly, de-modifying enzymes HDAC1-3 and SIRT1-3 exhibit both deacetylase and delactylase activities; SIRT2, for example, removes H3K18la and H4K8la modifications (33). Lactate and acetyl-CoA compete for the same lysine residues. In the acidic TME, lactate accumulation drives H3K18la to replace H3K18ac, activating immunosuppressive genes such as programmed death-ligand 1 (PD-L1). Conversely, under glucose-replete conditions, acetylation predominates, promoting oncogene transcription (35,36).

Kcr, another prominent Kac, serves key roles in diseases such as liver cancer (37) and glioblastoma (GBM) stem cells (38) by modulating histone structure and function. A previous study suggested potential synergistic roles for Kla and Kcr in processes such as neural differentiation and cell proliferation (39). However, due to its greater hydrophobicity, Kcr can antagonize Kla modifications in open chromatin regions; for example, H3K56la suppresses Kcr-mediated activation of inflammatory genes (40). Kla and phosphorylation mutually amplify oncogenic signals through positive feedback loops. Histone lactylation (such as H3K18la) activates genes encoding cell cycle kinases (for example TTK protein kinase and BUB1 mitotic checkpoint serine/threonine kinase B). Their protein products phosphorylate LDHA at Tyr239, enhancing LDHA activity and lactate production, promoting further lactylation (14). Similarly, AMPK phosphorylation of p300 at Ser89 enhances its lactyltransferase activity, establishing a metabolic stress-p300 lactylation amplification loop (34). Furthermore, transcription factor EB (TFEB) lactylation at K91 impedes binding via the action of the E3 ubiquitin ligase WW domain containing E3 ubiquitin protein ligase 2, reducing TFEB ubiquitination and degradation. This stabilization enhances autophagy and lysosomal biogenesis, supporting tumor survival (41).

Kla is intricately integrated within the intricate dynamic PTM network and is particularly interconnected with other types of lysine acylation (such as Kac and Kcr) via shared core enzymatic machinery (such as p300/CBP and HBO1 with dual lactyl/acyl transferase activity; HDACs/SIRTs with dual deacetylase/delactylase activity). This interdependence underpins the ‘metabolite-concentration-dependent substrate competition’ hypothesis: Fluctuations in metabolite abundance (such as lactate and acetyl-CoA) competitively regulate the balance between different types of acylation, with cascading effects, and pyruvate dehydrogenase complex component X acetylation inhibits lactate production, subsequently downregulating H3K56 lactylation (29,39). However, the downstream mechanistic effects of these interactions remain largely unknown. Critical unresolved questions include: Do Kla and Kac/Kcr directly compete for occupancy at identical lysine residues? How do the distinct chemical properties of the modifying groups (lactyl, acetyl and the more hydrophobic crotonyl) lead to the recruitment of specific reader proteins and functional divergence (such as the Brg1-specific recognition of H3K18la)? How are these interactions tissue- or tumor-type dependent?

For the emerging Kcr, evidence for functional synergy or antagonism with Kla in cancer is limited, and the differential impact of their chemical properties on chromatin remodeling and signal transduction is poorly understood. The hijacking of shared regulatory factors by drug-induced modifications (such as lysine isonicotinylation) highlights the sensitivity and complexity of the PTM network, yet the pathological importance of endogenous analogues remains unknown.

Current research often remains descriptive or focused on isolated pathways. Notable limitations include insufficient investigation of spatiotemporal dynamics, lack of rigorous causal validation and inadequate critical assessment of model systems and technological constraints. These gaps hinder a comprehensive understanding of the precise role of this sophisticated metabolic-epigenetic coupling network in tumorigenesis. Future research should employ tools such as site-specific mutagenesis, time-resolved omics and metabolic gradient models to evaluate the kinetics of inter-modification competition, identify specific effector molecules and assess the consequences of network perturbation. Overcoming the current fragmented understanding is essential to providing a solid theoretical foundation for the development of precision anticancer strategies targeting key nodes within the PTM network.

Lactylation serves as both a core effector and driver of metabolic reprogramming. By establishing self-reinforcing positive feedback loops, it not only directly couples glycolysis with epigenetic reprogramming but also maintains cancer stem cell properties and promotes angiogenesis. This multifaceted mechanism drives tumor growth, invasion and metastasis across multiple dimensions.

Lactylation directly couples glycolysis with epigenetic reprogramming, forming self-reinforcing pro-tumorigenic circuits. Histone lactylation serves as a critical link between metabolic reprogramming and transcriptomic dysregulation in cancer cells (4). In malignant cells, metabolic alterations induce fluctuations in lactate levels, which manifest as changes in histone lactylation. Conversely, shifts in the histone lactylation landscape reshape the transcriptomic profile to accommodate the metabolic reprogramming demands within the TME. This establishes a metabolic reprogramming-lactylation positive feedback loop that accelerates tumor progression. For example, in clear cell renal cell carcinoma (ccRCC), lactylation levels are markedly elevated compared with normal kidney tissue (50). This increase is particularly pronounced upon loss of the key tumor suppressor von Hippel-Lindau (VHL) protein. VHL deficiency leads to hypoxia-inducible factor (HIF) accumulation, which directly promotes lactate production via glycolysis. Furthermore, lactylation enhances the transcriptional activity of platelet-derived growth factor receptor β (PDGFRβ). Activation of the PDGFRβ signaling pathway subsequently elevates lactylation levels, establishing a self-reinforcing circuit that drives ccRCC progression (50). Similarly, in pancreatic cancer, lactate from TAMs induces lactylation of nucleolar and spindle-associated protein 1 (NUSAP1), upregulating its expression. NUSAP1 forms a transcriptional complex with c-Myc and HIF-1α. These transcription factors bind to the LDHA promoter, enhancing LDHA expression, thereby promoting glycolysis and increasing lactate production. This creates another positive feedback loop (51). Collectively, these metabolic reprogramming-lactylation positive feedback circuits serve a pivotal role in driving tumor growth and metastasis.

Tumor growth and metastasis are governed by multiple factors, including cancer stemness and tumor angiogenesis. Cancer stemness refers to the capacity of tumor cells for self-renewal and differentiation into a range of cell types, which is essential for tumor progression and dissemination. Activation of the NF-κB signaling pathway induces histone H3 lactylation, increasing expression of the long non-coding RNA LINC01127. LINC01127 sustains GBM stemness through the MAP4K4/JNK/NF-κB axis (52). Furthermore, Feng et al (53) demonstrated that liver cancer stem cells (LCSCs) exhibit elevated glycolytic flux, lactate accumulation and lactylation levels compared with HCC cells. Notably, histone H3K56la is closely associated with the tumorigenicity and stemness maintenance of LCSCs. High glycolytic flux provides the lactate substrate driving H3K9la/H3K56la modifications, while lactylation, in-turn, upregulates glycolytic enzyme expression. This establishes an LCSC-specific metabolic-epigenetic memory that perpetuates a self-sustaining loop.

As the circulatory system is a major route of metastasis, tumor angiogenesis is critically important for both tumor metastasis and growth. Lactate, functions as a potent pro-angiogenic factor and promotes angiogenesis through multiple mechanisms (54–56). Lactate activates the GPR81 receptor on endothelial cells, stimulating angiogenesis and subsequently promoting tumor cell proliferation and survival (55). Through HIF-dependent pathways, lactate, transported via MCT1, inhibits prolyl hydroxylases, thereby stabilizing HIF-1α. This stabilization enhances VEGF expression and angiogenesis. In HIF-independent pathways, lactate promotes angiogenesis via ROS generation and NF-κB/IL-8 signaling (54,55). Mounting evidence has established lactylation as a critical regulator of tumor angiogenesis. For example, Luo et al (57) demonstrated that lactylation of HIF1α at K672 promotes angiogenesis in prostate cancer by enhancing transcription of the cell migration-inducing and hyaluronan-binding protein gene. Furthermore, as previously discussed, NUSAP1 forms a transcriptional complex with c-Myc and HIF-1α that binds to the LDHA promoter, augmenting LDHA expression to drive angiogenesis and metastasis in pancreatic ductal adenocarcinoma (51).

Cellular senescence is characterized by irreversible cell cycle exit accompanied by distinct morphological and metabolic alterations, including activation of the senescence-associated secretory phenotype (SASP). The SASP entails secretion of bioactive mediators (chemokines, cytokines and proteases) that exert paracrine oncogenic effects within TME, driving neoplastic proliferation, apoptotic resistance, angiogenesis, metastatic dissemination and immune suppression (49). Pioneering work by Maekawa and Yamanaka (62) identified GLIS family zinc finger 1 (GLIS1) as a pluripotency-associated transcription factor capable of reprogramming both normal and senescent cells. During early reprogramming, GLIS1 directly binds glycolytic gene loci to activate their transcription while repressing somatic gene chromatin, inducing metabolic rewiring from OXPHOS to dominance of glycolysis with concomitant lipogenesis. This glycolytic surge increases intracellular acetyl-CoA and lactate pools, fueling secondary epigenetic modifications including H3K27 acetylation (H3K27ac) and H3K18 lactylation (H3K18la) at loci associated with pluripotency. These chromatin accessibility changes facilitate transcriptional reprogramming through structural relaxation (63). Notably, Rong et al (64) revealed that GLIS1 overexpression in exhausted HCC-infiltrating CD8⁺ T cells promotes T cell dysfunction via a serum/glucocorticoid regulated kinase 1-STAT3-PD-1 axis activation, mechanistically linking metabolic control to immune evasion.

Within the TME, lactate modulates interactions among a range of cell types, including tumor cells, CAFs, TAMs and TILs, to shape an immunosuppressive milieu conducive to tumor growth and immune evasion. This process is fundamentally associated with key hallmarks of cancer: Tumor-promoting inflammation, inducing angiogenesis and evading immune destruction.

Lactate-mediated polarization of TAMs toward the M2 phenotype constitutes a central mechanism in its promotion of tumor-associated inflammation. Beyond histone lactylation, multiple specific pathways have been elucidated. Wang et al (65) demonstrated that PCSK9 inhibition reduced M2 polarization by modulating MIF and lactate levels. Han et al (66) reported that D-lactate promotes M2-to-M1 transition through PI3K/AKT pathway suppression and NF-κB pathway activation. Liu et al (67) established that lactate stabilizes HIF-2α via mTORC1-dependent inhibition of the TFEB/ATP6V0d2 axis, enhancing expression of M2-associated genes (such as VEGF). Zhang et al (8) identified lactate binding to mitochondrial antiviral-signaling protein as an inhibitor of retinoic acid-inducible gene I signaling, indirectly facilitating M2 polarization. Lactate-induced histone lactylation functions as a ‘lactate clock’, enabling macrophages to acquire LPS tolerance and sustain M2-related gene expression (2,68). Collectively, these mechanisms program TAMs to exert immunosuppressive, pro-angiogenic and tumor-promoting functions.

Evading immune destruction, a defining hallmark of cancer (10), is garnering increasing attention. Lactate within the TME serves a pivotal role in tumor immune evasion. It not only drives the polarization of T cells and macrophages toward immunosuppressive phenotypes, such as promoting Treg differentiation and M2-type TAM formation, but also enhances the functionality of these immunosuppressive cells through multiple mechanisms, thereby facilitating tumor cell escape from immune surveillance (69).

Lactate amplifies immunosuppression by expanding the population and augmenting the activity of myeloid-derived suppressor cells (MDSCs), resulting in impaired cytotoxic T cell and natural killer cell function (70). Furthermore, lactylation modulates DNA repair capacity, indirectly promoting immune evasion. Li et al (71) demonstrated that glycolytic reprogramming enhanced X-ray repair cross-complementing protein 1 (XRCC1) lactylation at K247, promoting its nuclear translocation and DNA repair function, ultimately conferring resistance to radiotherapy. Similarly, Chen et al (72) found that nibrin (NBS1) lactylation markedly enhanced DNA repair efficiency. This enhanced genomic maintenance capability indirectly supports immune escape.

In summary, lactylation orchestrates immune evasion by constructing a multi-tiered immunosuppressive network through reprogramming TAM functionality, suppressing effector T cell activity, activating inhibitory immune cells (Tregs, MDSCs and PD-L1⁺ neutrophils), and bolstering tumor cell intrinsic resistance (via enhanced DNA repair). This highlights lactylation as a central metabolic-epigenetic mechanism underpinning tumor immune evasion, providing a compelling rationale for therapeutic strategies targeting lactylation to enhance immunotherapy efficacy.

Lactylation serves as a central metabolic-epigenetic coupling hub that simultaneously drives genomic instability, non-mutational epigenetic reprogramming and phenotypic plasticity. This dynamic adaptive capacity enables tumor cells to overcome differentiation barriers and acquire hallmark malignant progression capabilities under microenvironmental stress.

Genomic mutations fundamentally involve alterations in DNA sequences, including nucleotide additions/substitutions/deletions, single/double-strand breaks and structural rearrangements such as translocations, duplications or deletions.

Chen et al (73) demonstrated that MRE11 homolog, double strand break repair nuclease (MRE11), a core nuclease in DNA repair, undergoes robust lactylation catalyzed by the acetyltransferase CBP. Lactylation at MRE11-K673 enhances MRE11-DNA binding, thereby promoting DNA end resection and homologous recombination repair. Epigenetic alterations notably impact genomic stability through two primary mechanisms. DNA methylation dysregulation is where aberrant hyper/hypomethylation at regulatory regions can mimic mutational effects to drive carcinogenesis. Additionally, histone modification-mediated chromatin remodeling is where an altered chromatin architecture may induce chromosomal rearrangements and instability, disrupting cell cycle progression and checkpoint control. For example, p53 (the guardian of the genome) maintains genomic integrity. Zong et al (74) identified AARS1 as a lactate sensor and lactyltransferase that mediates global lysine lactylation in tumor cells, targeting key proteins including p53. Beyond proteins, lactylation may potentially occur on DNA/RNA sequences, analogous to documented mRNA acetylation (75).

Epigenetic reprogramming, alterations in gene expression without changes in DNA sequence, serves fundamental roles in development, differentiation and tissue homeostasis (49). Within the TME, aberrant conditions such as hypoxia and nutrient deprivation drive extensive epigenetic modifications that enable cancer cells to acquire hallmark malignant capabilities. Hypoxia-induced lactate accumulation suppresses ten-eleven translocation demethylase activity by reducing α-ketoglutarate levels (76). This leads to CpG island hypermethylation and subsequent silencing of tumor suppressor gene promoters (such as CDK inhibitor 2A), a mutation-independent mechanism enriched in gliomas and CRC (63,77). In IDH-mutant gliomas, lactylation-mediated metabolic dysregulation further induces aberrant methylation of CCCTC-binding factor insulators, reducing oncogene expression (such as PDGFRA) to drive tumorigenesis. Stromal cells within the TME, including CAFs, innate immune cells and endothelial cells, undergo non-genetic epigenetic reprogramming upon recruitment to solid tumors, enhancing their pro-tumorigenic functions. Lactate additionally facilitates cancer cell migration by modulating integrin binding to extracellular matrix components (78). Furthermore, CAFs alter cancer cell NAD⁺/NADH ratios via lactate shuttling, activating SIRT1-dependent PPARG coactivator 1a to increase mitochondrial biogenesis and activity, thereby remodeling cancer cell metabolism (79).

The relationship between lactylation and tumor phenotypic plasticity, an emerging cancer hallmark enabling malignant progression through evasion of terminal differentiation, remains incompletely elucidated (49). Phenotypic plasticity subverts normal developmental processes wherein terminally differentiated cells exit the cell cycle irreversibly, instead promoting dedifferentiation (progenitor-like reversion), differentiation blockade (progenitor-stage arrest) or trans-differentiation (heterologous trait acquisition). Mechanistic evidence reveals context-dependent functions. In BRAF inhibitor-resistant melanoma, lactate accumulation induces lysine-specific histone demethylase 1A (LSD1)-K503 lactylation, impeding tripartite motif-containing protein 21-mediated degradation to stabilize LSD1-FosL1 complexes, which suppress transferrin receptor transcription and confer ferroptosis resistance, and this is reversed by LSD1 inhibitors (80). GBM utilizes GTP cyclohydrolase I-synthesized lactoyl-CoA to cooperate with p300, driving H3K18la-mediated growth/differentiation factor 15 upregulation, and this sustains cancer stemness and radioresistance (81).

Age-related macular degeneration models further demonstrate that histone lactylation and alkB homolog 3, a-ketoglutarate dependent dioxygenase-driven glycolysis form a feedforward loop accelerating mesenchymal transition and fibrosis (82). Beyond oncology, lactylation remodels chromatin accessibility during embryonic stem cell differentiation toward extraembryonic endoderm and coordinates mesenchymal-epithelial transition in somatic reprogramming. Notably, tissue-specific functional paradoxes exist; loss of α-major histocompatibility complex-K1897 lactylation exacerbates heart failure in cardiomyocytes (83), while neuronal arrestin b1-K195 lactylation induces S100A9-mediated mitochondrial apoptosis (84).

These opposing outcomes underscore the microenvironmental context, including lactate gradients and substrate specificity, as determinants of the functional directionality of lactylation. The spatiotemporal dynamics of lactylation constitute a master regulator of phenotypic plasticity. Future research should integrate high-resolution spatiotemporal mapping (single-cell lactylome profiling across TME niches), multi-omics dynamic modeling (lactylation-metabolism-oscillation coupling) and context-specific delivery tools (precision interventions) to elucidate the global roles of lactylation in TME heterogeneity, cell fate decisions and therapeutic resistance, providing novel paradigms to overcome plasticity-driven treatment failure and metastasis.

Table I systematically summarizes the lactylation sites, regulatory mechanisms and clinical implications across key cancer hallmarks, providing a comprehensive overview of its multifaceted roles.

Targeting lactylation has emerged as a promising anticancer strategy, offering novel therapeutic avenues for drug development. Current approaches focus on key nodes in lactate metabolism, transport and modification. Peng et al (96) demonstrated that inhibiting solute carrier family 16 member 1, a lactate transporter that is upregulated in pancreatic cancer and associated with lactylation levels, reduced intracellular lactate levels, suppressed lactylation and inhibited tumor proliferation and migration. Similarly, BRAFV600E inhibitors decreased glycolysis and lactylation, inducing cell cycle arrest in thyroid cancer, suggesting potential synergy with existing targeted therapies through modulation of a glycolysis-lactylation axis (94).

LDHA, the key enzyme converting pyruvate to lactate, represents another critical target. Its upregulation is associated with a poor prognosis across several types of cancer. The competitive inhibitor oxamate reduced cancer proliferation by blocking glycolysis (99), while gossypin directly inhibited LDHA activity, decreasing lactate accumulation and promoting apoptosis (100). However, LDHA inhibitors face notable limitations: Off-target effects and unpredictable side effects from non-selective inhibition necessitate strategies to improve drug specificity and a deeper mechanistic understanding. Emerging agents aim to address these challenges through more precise modulation. Simeprevir and oxamate inhibit LDHA to reduce NBS1-K388 lactylation, whereas L-alanine competes with lactate for AARS1 binding. These targeted approaches show notable potential for advancing lactylation-based cancer therapies.

Tumor resistance remains a major barrier to effective cancer therapy, with emerging evidence implicating lactylation as a key mediator. Chen et al (73) demonstrated that MRE11 lactylation enhances DNA-binding capacity, promoting homologous recombination repair and chemoresistance in a lactate-abundant TME. Similarly, NBS1 lactylation markedly increases DNA repair efficiency, while XRCC1-K247 lactylation facilitated nuclear translocation to confer chemo/radioresistance in GBM (71,72). These findings establish lactylation as a promising therapeutic target to overcome treatment resistance.

Proof-of-concept studies validate this approach; a cell-penetrating peptide blocking MRE11-K673 lactylation sensitized tumors to cisplatin and PARP inhibitors by inhibiting DNA repair (73). Additionally, the small molecule D34-919 disrupted an aldehyde dehydrogenase 1 family, member A3-pyruvate kinase M1/2 interaction, reducing lactate production and XRCC1 lactylation, thus restoring radiosensitivity in GBM (71). These targeted strategies demonstrate that inhibiting specific lactylation events can reverse treatment resistance mechanisms, providing a rational foundation for combining lactylation-directed therapies with conventional cancer treatments. Further investigations should focus on optimizing lactylation-targeted agents for clinical translation.

Emerging evidence has established lactylation as a pivotal epigenetic regulator of resistance to cancer immunotherapy. Tumor-derived lactate drives immunosuppression within the TME through lactylation-dependent mechanisms, including moesin-K72 lactylation, which enhances Treg immunosuppressive activity (101). Critically, reducing TME lactate levels improves anti-PD-1 efficacy, positioning lactate modulation as a promising immunotherapeutic adjuvant (101). In HCC, lactate activates the MCT1/NF-κB/cyclooxygenase 2 (COX-2) axis to generate PD-L1⁺ neutrophils that mediate immune evasion, a phenotype reversed by COX-2 inhibition with celecoxib, synergizing with Lenvatinib (45). Similarly, STAT5-driven glycolytic flux in acute myeloid leukemia (AML) elevates histone lactylation, upregulating PD-L1 and impairing CD8⁺ T cell function. PD-1/PD-L1 blockade restores T cell activity in STAT5-high AML models, supporting biomarker-guided immunotherapy for glycolytic subtypes (102).

Pharmacological inhibition of lactate transport via AZD3965 (an MCT1 inhibitor) disrupts immunosuppression and attenuates tumor growth (103), while genetic lactylation inhibition overcomes VEGF resistance in CRC (88). These findings highlight the therapeutic promise of dual-targeting lactylation pathways and immune checkpoints. Current strategies targeting lactate synthesis (LDHA inhibitors), transport (MCT blockers) and lactylation modifiers require improved precision. Future efforts should prioritize developing site-specific lactylation inhibitors and combinatorial regimens leveraging metabolic-immune crosstalk. Despite promising preclinical validation of the chemosensitizing role of lactylation, translational challenges, including tissue-specific dynamics and off-target effects, necessitate deeper mechanistic exploration to improve clinical translation.

Current therapeutic strategies targeting lactylation focused on three pillars: Disrupting lactate metabolism (LDHA/MCT inhibition), reversing treatment resistance (blocking lactylation of DNA repair proteins) and overcoming immunosuppression (reprogramming Tregs/myeloid cells). However, notable challenges remain in utilizing these approaches clinically. Firstly, the mechanistic understanding in vitro and in animal models often fails to translate effectively, as exemplified by LDHA inhibitors paradoxically inducing protective autophagy, which enhances drug resistance. Secondly, targeting specificity conflicts with physiological complexity, as demonstrated by MCT1 inhibitor AZD3965 simultaneously impairing T cell antitumor functions. Thirdly, static interventions ignore the spatiotemporal heterogeneity of lactylation dynamics, particularly regarding optimal dosing windows. Notably, lactate metabolism targeting (such as oxamate inhibiting LDHA) frequently overlooks compensatory metabolic pathways. Resistance-reversal strategies (such as targeting MRE11-K673la) lack tissue selectivity, risking collateral damage to normal DNA repair mechanisms. Immunotherapy combinations often disregard the dual regulatory roles of lactylation in the TME, where suppressing Treg lactylation may destabilize immune homeostasis.

Future research must advance toward dynamic precision modulation: Developing spatiotemporally responsive delivery systems (such as pH-sensitive nanocarriers with SIRT2 activators) to inhibit oncogenic lactylation (for example MRE11-K673la) while sparing normal tissues; integrating multi-omic biomarkers (such as plasma exosomal H3K18la or PET-based p300 activity tracing) for patient stratification and triple-targeting (production-transportation-‘reader’) combination therapies; and pioneering innovative tools such as CRISPR-dCas9-mediated site-specific delactylation and microbiome-engineered bacteria modulating gut lactylation. Collectively, these advances will transition lactylation-targeted therapy from single-node inhibition toward artificial intelligence-guided reprogramming of epigenetic-metabolic networks, ultimately establishing curative paradigms for cancer treatment.