Protein lactylation in cancer: principles, programmes and therapeutic opportunities

Abstract

Lactylation is a recently identified metabolism-associated post-translational modification that provides a mechanistic link between tumor metabolic reprogramming and epigenetic regulation. Although aberrant lactate accumulation in tumor tissues has long been recognized, a comprehensive and unified understanding of how lactate-derived modifications contribute to tumor initiation and progression remains lacking. Here, we use lactate metabolism as a conceptual framework to systematically review the biogenesis and regulatory networks of lactylation, with a particular focus on its functions and underlying molecular mechanisms in key malignant processes, including tumor proliferation, invasion and metastasis, angiogenesis, immune evasion, radiotherapy resistance and systemic therapy resistance. Furthermore, we review emerging anti-tumor therapeutic strategies targeting lactate metabolism and tumor lactylation, highlighting that glucose metabolism–driven lactate accumulation and lactylation play a pivotal role in sustaining tumor cell survival and immunosuppressive phenotypes. Inhibition of lactate metabolism markedly attenuates tumor-associated lactylation and exhibits substantial synergistic efficacy when combined with other anti-tumor therapies. Overall, this work advances a systematic understanding of the roles of lactylation in tumor malignant progression and provides an important conceptual and theoretical foundation for the development of novel cancer therapeutic strategies targeting protein lactylation.

Introduction

Lactate is a by-product of glycolysis and was long regarded as a metabolic waste product. This view began to shift in the twentieth century as advances in metabolic research — particularly Otto Warburg’s 1927 description of aerobic glycolysis in tumor cells (the “Warburg effect”), which is accompanied by substantial lactate production — renewed interest in lactate as a biologically active metabolite within the tumor microenvironment (TME) [1]. Accumulating evidence now indicates that lactate is not merely an end product of glycolysis but an active metabolite that sustains cellular physiology. Lactate can serve as a carbon and energy source: cells import extracellular lactate via monocarboxylate transporters (MCTs), and lactate dehydrogenase B (LDHB) oxidizes lactate to pyruvate, which subsequently fuels the tricarboxylic acid cycle and supports bioenergetic demands [2]. In addition, lactate can act as a signaling molecule by engaging cell-surface receptors, thereby promoting tumor-cell invasion, metastasis and angiogenesis [3]. Within the TME, lactate accumulation contributes to extracellular acidification, lowering pH and perturbing acid–base homeostasis. This acidic milieu impairs immune-cell function and thereby facilitates tumor immune evasion [4]. More recently, lactate has emerged as a key metabolite that can drive post-translational modifications (PTMs) [5].

PTMs are covalent modifications of specific amino acid residues that occur after protein synthesis, including methylation, acetylation and ubiquitination, among others. Acting as rapid and often reversible regulatory switches, PTMs tune protein activity, stability, localization and protein–protein interactions, thereby rewiring signaling networks. Pervasive across biology, PTMs shape diverse processes, including cellular differentiation and development, environmental adaptation and disease pathogenesis [6, 7]. In 2019, a lactate-linked modification termed lysine lactylation (kla) was reported [8], showing that glycolysis-derived lactate can serve as a donor to covalently modify histone lysine residues and thereby influence chromatin organization and gene expression. Lactylation was initially linked to macrophage activation and polarization, highlighting a direct interface between cellular metabolism and epigenetic control [8, 9]. Subsequent studies have further shown that lactylation is not restricted to histones and can also occur on non-histone proteins [10]. Lactylation shares features with other PTMs but also has distinct properties [10]. Like acetylation, methylation and ubiquitination, lactylation primarily targets lysine residues; however, it is defined by the addition of a lactyl group, which differs chemically from the moieties installed by other lysine-directed PTMs [11–14]. Acetylation is the covalent addition of an acetyl group to lysine residues, which neutralizes their positive charge and can modulate chromatin accessibility and protein function. For example, acetylation of p53 influences its transcriptional activity and stability [12]. Methylation entails the addition of one or more methyl groups to lysine or arginine residues, Unlike acetylation, methylation generally has little effect on the net charge of proteins, but it can alter surface recognition motifs and thereby modulate molecular interactions, including protein–protein interactions. In chromatin, methylation is a key regulatory mark that influences transcriptional activity in a context-dependent manner [13]. Ubiquitination is ubiquitin-like conjugation pathways in which ubiquitin is covalently attached to target proteins to alter their stability. Polyubiquitination, particularly via K48-linked chains, classically targets proteins for proteasomal degradation [15, 16]. By contrast, lactylation installs a lactyl group on lysine residues and can modulate protein stability or reshape transcriptional programming. Functionally, lactylation resembles acetylation in that lactylation of histone lysine residues can reduce positive charge and alter chromatin organization, thereby influencing transcriptional outputs [11]. However, lactylation is distinguished by the origin of its modifying group: the lactyl moiety is derived from lactate, linking this mark directly to glycolytic flux, in contrast to other modifications such as acetylation and ubiquitination. Among the factors that regulate PTMs, the enzymatic regulators of lactylation most closely resemble those of acetylation. Indeed, several acetylation-regulating enzymes, including p300/ CREB-binding protein (CBP) and histone deacetylases (HDACs), have also been implicated in lactylation regulation. By contrast, methylation is mainly controlled by lysine methyltransferases (KMTs), protein arginine methyltransferases (PRMTs), and demethylases such as LSD and KDM family members. Ubiquitination is mediated by the sequential actions of E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases, whereas deubiquitination is primarily catalysed by deubiquitinases, including members of the USP family (Table 1). Current evidence indicates that lactate-driven lactylation extends beyond host responses to infection and also shapes key processes in the TME, including metabolic reprogramming, immune evasion and tumor progression. This shift has repositioned lactate from a metabolic by-product to a signaling and chromatin-linked metabolite, placing it at the interface of metabolism and PTMs.

Table 1.

Overview of protein post-translational modifications

Modification	Modified residue(s)	Added group	Functional features	Key regulators (writers/erasers/readers)	Reference
Lactylation	Lys (K)	Lactyl (–CO–CH(OH)–CH₃)	Neutralizes lysine positive charge; modulates chromatin accessibility and transcription; alters enzyme activity, protein stability and subcellular localization	Writers: EP300/CBP, AARS1/2; Erasers: HDACs	[10]
Acetylation	Lys (K)	Acetyl (–COCH₃)	Neutralizes lysine positive charge; regulates chromatin activity and transcription; modulates protein activity and interactions	Writers: HATs/KATs; Erasers: HDACs, Sirtuins	[12]
Methylation	Lys (K), Arg (R)	Methyl (–CH₃)	Modulates protein–protein interactions and functional states; controls subcellular localization and protein stability; specifies distinct methylation states (me1/me2/me3; ADMA/SDMA)	Writers: KMTs, PRMTs; Erasers: LSD1 (KDM1A), JmjC-KDMs	[13]
Ubiquitination	Lys (K) (also N-terminus)	Ubiquitin (76-aa protein)	Targets proteins for proteasomal degradation; linkage-specific roles in signaling, trafficking and DNA repair	E1–E2–E3 (RING E3s); DUBs (USPs)	[15, 16]

Cancer is a leading cause of death from disease worldwide and is the second leading cause of death globally [17]. Malignant proliferation, invasive and metastatic spread, immune evasion, resistance to radiotherapy and systemic therapies, and collectively underpin the clinical challenge of treating cancer [18]. Elucidating the mechanisms that sustain malignant phenotypes and developing effective intervention strategies have long been central goals of cancer research. Growing evidence implicates protein lactylation as a contributor to tumor progression [19]. By rewiring transcriptional programming and signaling networks, lactylation can promote oncogenic gene-expression states and thereby facilitate malignant growth and dissemination [19].

In this review, we summarized the regulatory landscape of protein lactylation and synthesized current evidence for its roles in tumor proliferation, invasion and metastasis, angiogenesis, immune evasion and resistance to radiotherapy and systemic therapies, highlighting underlying molecular mechanisms. We found that lactate-driven protein lactylation may be a key contributor to tumor therapy resistance. Accordingly, combining metabolic inhibitors—particularly those targeting glucose metabolism—with other anticancer therapies may offer a promising therapeutic strategy.

The regulatory landscape of lactylation

Lactylation is a recently described post-translational modification in which a lactyl group derived from lactate is covalently installed on the ε-amino group of lysine, generating Kla. First reported in 2019, lactylation links cellular lactate metabolism to protein regulation and has been detected across diverse cell types, with emerging roles in multiple biological processes [20]. Chemically, lactylation is a lysine acylation in which a lactyl moiety (–CO–CH(OH)–CH₃) is covalently linked to the ε-amino group of lysine via an amide bond. Conceptually, lactylation can be regulated through canonical epigenetic circuitry, with writers, erasers and putative readers coordinating its installation, removal and interpretation, while lactylation may also arise through non-enzymatic chemistry under metabolically permissive conditions (Fig. 1).

Fig. 1.

Overview of the biogenesis and regulation of protein lactylation. Enzymatic modification: Lactate generated by glycolysis or imported from the extracellular milieu is converted to lactyl-CoA by a lactyl-CoA–producing enzyme (putative lactyl-CoA synthase). The lactyl moiety is then transferred to lysine residues on histone and non-histone proteins by writer enzymes, establishing lysine lactylation. Erasers enzymes remove lactyl marks, whereas reader proteins recognise lactylated lysines to mediate downstream functional outcomes. Non-enzymatic modification: The glycolytic by-product methylglyoxal (MGO) reacts with glutathione through glyoxalase 1 (GLO1) to generate S-lactoylglutathione (LGSH), which can serve as an acyl donor in non-enzymatic lysine lactylation. LGSH is subsequently hydrolysed by glyoxalase 2 (GLO2) to yield D-lactate and glutathione (GSH), replenishing the cycle. Abbreviations: MGO, methylglyoxal; LGSH, S-lactoylglutathione; GLO1, glyoxalase 1; GLO2, glyoxalase 2; GSH, glutathione

Enzymatic modification

Enzyme-mediated lactylation is a regulated process coordinated by dedicated enzymes that function as “writers”, “erasers” and putative “readers”. Writers catalyze the installation of lactyl groups on lysine residues, erasers remove these marks, and readers recognize lactylated sites to translate the modification into downstream functional outcomes [21]. Intracellular L-lactate can be generated through two major routes. First, extracellular glucose is metabolized through glycolysis to produce pyruvate, which is then reduced to L-lactate by lactate dehydrogenase A (LDHA). Second, L-lactate can be imported directly from the extracellular milieu via MCTs [22]. Recent work identifies GTP-specific succinyl-CoA synthetase (GTPSCS) as a nuclear lactyl-CoA synthetase that supports histone lactylation. In the nucleus, GTPSCS can associate with the acetyltransferase p300, promoting histone lactylation and upregulating lactylation-linked gene-expression programs [23]. Non-histone lactylation may also be coupled to lactyl-CoA availability, with writer enzymes catalyze the installation of lactyl groups on lysine residues of non-histone proteins [5]. Recent studies have uncovered an enzyme-mediated route for lactylation in which alanine–tRNA synthetases AARS1 and AARS2 function as intracellular L-lactate sensors and ATP-dependent lactyltransferases. By directly binding L-lactate, AARS1/2 catalyze a two-step reaction to install lactyl groups on lysine residues of target proteins, thereby expanding the enzymatic “writers” repertoire for protein lactylation [24, 25]. These findings suggest that lactylation can be driven by lactate availability and that formation of lactyl-CoA may not be an obligate intermediate for all enzymatic routes.

Multiple enzymes have been proposed to function as lactylation “writers”, many of which are classical lysine acyltransferases. These include AARS1/2, the p300/CBP family, the MYST family (for example, MOF/KAT8, HBO1/KAT7 and TIP60/KAT5) and the Gcn5-related N-acetyltransferase (GNAT) family (for example, GCN5/KAT2A and PCAF/KAT2B) [26]. Among the proposed writers, p300 and KAT8 function as lysine acyltransferases and have been implicated in both histone and non-histone lactylation. Collectively, these enzymes mediate protein lactylation by installing lactyl groups on lysine residues through ATP-dependent or ATP-independent routes.

By contrast, “erasers” remove lactylation marks from lysine. In mammals, HDACs have emerged as major de-lactylation enzymes capable of removing lysine L-lactylation (K(L)la) and D-lactylation (K(D)la). Mammalian deacetylases fall into two broad families: Zn²⁺-dependent HDACs (HDAC1–11; classes I, II and IV) and NAD⁺-dependent sirtuins (SIRT1–7; class III) [27]. Historically, Zn²⁺-dependent HDACs were viewed as predominantly histone-directed enzymes, whereas sirtuins were thought to preferentially deacylate non-histone substrates in the cytoplasm and nucleus, implying complementary functions. More recent evidence, however, indicates that sirtuins also contribute to the removal of histone lactylation [28]. Recent work shows that HDAC1–3 possess robust de-lactylation activity in cells and in vitro using purified proteins, with particularly strong activity against K(D)la [29]. Although HDACs appear to preferentially remove K(L)la, the mechanisms governing K(L)la turnover may differ from those involved in K(D)la removal. Notably, K(L)la erasure has been proposed to depend on nuclear cross-talk among multiple molecular components, potentially involving chromatin context and multiprotein complexes [29].

Reader proteins recognize lactyl-lysine marks and translate them into downstream functional outputs, for example by recruiting chromatin regulators or modulating signaling pathways [30]. Although the repertoire of bona fide lactylation readers remains limited, recent studies have begun to define reader proteins that selectively bind histone lactylation. In cervical cancer, double PHD fingers 2 (DPF2) has been identified as an H3K14 lactylation (H3K14la) effector: DPF2 binds H3K14la and co-localizes with this mark at promoters, thereby modulating transcriptional programming that support tumor cell survival [31]. A study in pluripotent stem-cell models reported that Brg1 associates with H3K18 lactylation (H3K18la) and is enriched at promoters of pluripotency-related genes, thereby modulating their transcriptional programming. These findings nominate Brg1 as a candidate reader/effector of H3K18la during pluripotency regulation [32]. The role of lactylation “readers” in the nervous system is also beginning to emerge. In astrocytes following subarachnoid haemorrhage (SAH), bromodomain-containing protein 4 (BRD4) has been implicated in the regulation of H4K8 lactylation (H4K8la), as BRD4 silencing markedly alters H4K8la levels [33]. BRD4 is an epigenetic co-regulator that binds acetylated chromatin and enhancer elements to exert potent control over transcription. These properties raise the possibility that BRD4 may also function as a lactylation “reader” in specific contexts [33]. Together with writers and erasers, readers help set the dynamics and steady-state levels of lysine acylation marks within cells, thereby shaping cellular phenotypes. However, the identity and mechanism of lactylation readers remain incompletely defined, highlighting a key knowledge gap in the field.

Non-enzymatic modification

Non-enzymatic lactylation refers to D-lactylation that arises from reactive glycolytic by-products, in which D-lactate is generated from methylglyoxal (MGO), a glycolysis-derived α-ketoaldehyde. In Warburg-like cancer cells, enhanced glycolysis promotes MGO accumulation, which is channeled into the glyoxalase system to form S-D-lactoylglutathione (D-lactyl-GSH; lactoylglutathione, LGSH). LGSH can then undergo non-enzymatic S-to-N acyl transfer to lysine residues on proteins, generating K(D)la [34]. Further evidence suggests that lactylation can also proceed via a passive, non-enzymatic acyl-transfer route in which LGSH serves as a reactive acyl donor, and LGSH abundance is controlled by glyoxalase 2 (GLO2). Specifically, MGO rapidly reacts with glutathione (GSH) and is converted by glyoxalase 1 (GLO1) into LGSH, thereby promoting predominantly non-histone D-lactylation. In parallel, GLO2 hydrolyses LGSH to regenerate GSH and produce D-lactate, and this balance constrains the extent of non-enzymatic acyl transfer from LGSH to lysine residues on target proteins [35]. Given the limited evidence currently available for D-lactylation, the lactylation-mediated regulatory mechanisms discussed in this review mainly refer to L-lactylation.

Roles of lactylation in cancer

Malignant tumor growth and metastatic invasion are central drivers of cancer progression. A hostile TME further fuels this process by promoting angiogenesis and enforcing local immunosuppression. Treatment resistance has become a major obstacle in clinical oncology. Mounting evidence implicates epigenetic alterations in tumor development, progression and therapy resistance, highlighting epigenetic regulation as a tractable target for improving cancer treatment. Lactylation is an emerging epigenetic modification that contributes to tumor progression (Tables 2 and 3). Here we discuss how lactylation shapes malignant phenotypes, focusing on tumor proliferation, invasion and metastasis, angiogenesis, immune evasion, and resistance to radiotherapy and systemic therapies.

Table 2.

Evidence-based summary of histone lactylation in cancer

Tumor type	Route	Substrate(site)	Lactate source	Detection method	Biological functions	Evidence source	Reference
Breast cancer	L-lactylation	H3 (K18)	Tumor glycolysis, TME-derived	WB (specific kla) ChIP-qPCR; IHC	Promote proliferation, Aggravate metastasis, Confer doxorubicin resistance	Cell line Animal Clinical tissue	[36–40]
Ovarian cancer	L-lactylation	H3 (K18) H4 (K12)	Tumor glycolysis TME derived	WB (specific kla); IHC	Promote proliferation; Confer niraparib resistance	Cell lines Clinical tissue	[39, 41, 42]
Gastric cancer	L-lactylation	H3 (K18)	TME derived	WB (pan-kla, specific kla)	Promote proliferation, Aggravate metastasis	Cell lines Animal	[43]
head and neck squamous cell carcinoma	L-lactylation	H3 (K18) H3 (K9)	Tumor glycolysis	WB (pan-kla, specific kla); IHC	Promote metastasis, Facilitate immune escape	Cell line Animal Clinical tissues	[44–48]
Colorectal cancer	L-lactylation	H3 (K18) H3 (K9)	Tumor glycolysis	WB (pan-kla, specific kla); IHC	Aggravate metastasis, Facilitate immune evasion, Enhance radioresistance Enhance bevacizumab resistance;	Cell line Animal Clinical tissues	[49–54]
Hepatocellular carcinoma	L-lactylation	H3 (K18) H3 (K14)	Tumor glycolysis ablation	WB (pan-kla, specific kla); ChIP-qPCR; IHC	Aggravate Metastasis, Facilitate immune evasion, Enhance radioresistance; Confer 5-FU resistance; Confer lenvatinib resistance; Confer immunotherapy resistance	Cell line Animal Clinical tissues	[46, 55–62]
Bladder cancer	L-lactylation	H3 (K18)	Tumor glycolysis	WB (pan-kla, specific kla); ChIP-qPCR;	Aggravate metastasis, Enhance cisplatin resistance	Cell line Animal	[55, 56, 63]
Melanoma	L-lactylation	H3 (K18)	Tumor glycolysis	WB (pan-kla, )	Promote angiogenesis,	Cell line Animal	[52, 64]
Oral squamous cell carcinoma	L-lactylation	H4 (K12)	Tumor glycolysis	WB (pan-kla, specific kla); ChIP-qPCR;	Facilitate immune evasion	Cell line Animal	[65, 66]
Small cell lung cancer	L-lactylation	H3 (K18)	Tumor glycolysis	WB (pan-kla, specific kla); ChIP-qPCR;	Facilitate immune evasion	Cell line Animal	[67, 68]
Non-small cell lung cancer	L-lactylation	H3 (K18)	Tumor glycolysis	WB (pan-kla, specific kla); ChIP-qPCR;	Facilitate immune evasion	Cell line Animal	[69–72]
Glioma	L-lactylation	H3 (K18) H3 (K9)	Tumor glycolysis	WB (pan-kla, specific kla); ChIP-seq ChIP-qPCR; IHC	Facilitate immune evasion Enhance radioresistance, Enhance temozolomide resistance;	Cell line Animal Clinical tissues	[73–77]

Abbreviations: TME tumor microenvironment, WB western blotting, kla lysine lactylation

Table 3.

Evidence landscape of non-histone lactylation in cancer

Tumor type	Route	Substrate(site)	Lactate source	Detection method	Biological function	Evidence source	Reference
Lung cancer	L-lactylation	IGF1R, HAT1 (K15), ku70/80, RPA1, Mic60 (K282), SOX9, APOC2 (K70)	Tumor glycolysis	WB (pan-kla, IP-kla, specific kla antibody), MS, site-mutation, IHC	Promote proliferation; Enhance radioresistance; Enhance EGFR-TKIs resistance	Cell line Animal Clinical tissues	[45, 67, 78–83]
Colorectal cancer	L-lactylation	eEF1A2 (K408), β-catenin, RIG-I; XLF (K288)	Tumor glycolysis Escherichia coli TME derived lactate	WB (pan-kla, IP-kla, ), MS, site-mutation, IHC	Promote proliferation; Enhance Chemotherapy resistance; Enhance oxaliplatin resistance	Cell line Animal Clinical tissues	[49, 69, 84–88]
Cervical cancer	L-lactylation	G6PD (K45), DCBLD1 (K172), ANTXR (K453)	Tumor glycolysis TME derived lactate	WB (pan-kla, IP-kla, ), MS, site-mutation,	Promote proliferation, Aggravate metastasis	Cell line Animal	[50, 70, 85, 88, 89]
Gastric cancer	L-lactylation	YAP (K90), NSUN2 (K508), PCBP2 (k115)	Tumor glycolysis	WB (pan-kla, IP-kla, specific kla antibody), MS, site-mutation, IHC	Promote proliferation; Enhance Doxorubicin resistance; Enhance oxaliplatin resistance	Cell line Animal Clinical tissues	[24, 66, 90, 91]
Gallbladder carcinoma	L-lactylation	YY1 (K183) BLM (K24)	Tumor glycolysis	WB (pan-kla, IP-kla), ChIP-qPCR	Aggravate metastasis DNA-damaging thermotherapy resistance	Cell line	[71, 73]
Renal cell carcinoma	L-lactylation	MDH2 (K239), YTHDC1 (K82),	Tumor glycolysis	WB (pan-kla, IP-kla, specific kla antibody), MS, site-mutation	Aggravate metastasis	Cell line Animal	[53, 72, 74, 92]
Breast cancer	L-lactylation	PRMT1 (K134/145), MRE11 (K673), METTL3 (K27)	Tumor glycolysis	WB (pan-kla, IP-kla, ), MS, site-mutation	Aggravate Metastasis; Enhance cisplatin resistance	Cell line Animal	[47, 75, 78, 93, 94]
Hepatocellular carcinoma	L-lactylation	Rab7A, ASH2L (K312); IGF2BP3 (K76); PRDX1 (K67)	Tumor glycolysis	WB (pan-kla, IP-kla, specific kla antibody), MS, site-mutation	Aggravate metastasis, Promote angiogenesis; Enhance lenvatinib/plantinum-based resistance; Enhance regorafenib resistance	Cell line Animal Clinical tissues	[58, 95–100]
Glioma	L-lactylation	VEGFR2, VE-cadherin, YY1 (K183), XRCC1 (K247)	Tumor glycolysis	WB (pan-kla, IP-kla, specific kla antibody), MS, site-mutation	Promote proliferation; Aggravate metastasis; Promote angiogenesis; Enhance temozolomide resistance;	Cell line Animal	[54, 79, 93, 101, 102]
Prostate cancer	L-lactylation	HIF-1	Tumor glycolysis	WB (pan-kla, IP-kla), ChIP-qPCR	Promote angiogenesis; Promote vascular mimicry	Cell line Animal	[103, 104]
Pancreatic ductal adenocarcinoma	L-lactylation	ENSA (K63)	TME derived lactate	WB (pan-kla, IP-kla, specific kla antibody), MS, site-mutation	Accelerate Immune evasion; Enhance immunotherapy resistance;	Cell line Animal Clinical tissues	[105, 106]
Ovarian cancer	L-lactylation	RAD51 (K73)	Tumor glycolysis	WB (pan-kla, IP-kla), MS, site-mutation	Enhance cisplatin resistance	Cell line Animal	[82, 107]
Bladder cancer	L-lactylation	BLM (K24)	Tumor glycolysis	WB (pan-kla, IP-kla, specific kla antibody), MS, site-mutation	Enhance DNA-damaging chemotherapy resistance	Cell line Animal Clinical tissues phase I study	[102, 108]

Abbreviations: TME tumor microenvironment, WB western blotting, kla lysine lactylation

Proliferation

Uncontrolled tumor proliferation is a primary driver of malignant progression and poor clinical outcomes [36]. Protein lactylation exerts significant regulatory effects on malignant tumor proliferation (Fig. 2). Histones are core chromatin proteins that package DNA into nucleosomes and higher-order structures, thereby shaping transcriptional output. PTMs on histone residues can alter local electrostatics and chromatin accessibility, tuning histone–DNA interactions and gene expression. Histones are prominent substrates for lactylation. Lactylation of histone lysine residues neutralizes their positive charge, weakening histone–DNA interactions and relaxing chromatin. This increases DNA accessibility, facilitating transcription-factor binding and transcriptional activation. Histone lactylation was the first described form of protein lactylation and provides a mechanistic link between lactate metabolism and chromatin-dependent gene regulation [37]. In breast cancer, the potassium two-pore domain channel subfamily K member 1 (KCNK1) promotes histone H3K18la by binding to and activating LDHA. This activates a transcriptional programming that includes upregulation of LDHA itself, establishing a feedforward loop that enhances glycolysis and lactate production. Consequently, KCNK1–LDHA signaling supports breast cancer cell proliferation, invasion and metastasis [38]. In addition, H3K18la has been shown to potentiate c-Myc-driven proliferation in breast cancer cells [39]. In ovarian cancer, lactate promotes histone H3K18la in macrophages, inducing CCL18 expression and thereby enhancing ovarian cancer cell proliferation and migration [41]. Lactate in the TME drives dynamic histone H3K18la, which in turn activates VCAM1 transcription in gastric cancer cells. VCAM1 then promotes gastric cancer cell proliferation and migration through AKT–mTOR signaling [43]. Beyond histones, lactylation of non-histone proteins can also influence tumor cell proliferation. The insulin-like growth factor 1 receptor (IGF1R) is a transmembrane receptor tyrosine kinase that has central roles in tumorigenesis, metabolic regulation and drug resistance [44]. In lung cancer, lactylation of IGF1R stabilizes the receptor, promoting glycolysis and lactate production. This establishes a positive feedback loop that further reinforces IGF1R lactylation, ultimately driving lung cancer cell proliferation [45]. In colorectal cancer (CRC), the lysine acetyltransferase KAT8 enhances eEF1A2 activity by promoting its lactylation at Lys408. This augments translational capacity and protein synthesis, thereby driving CRC cell proliferation [49]. Hypoxia-driven glycolysis has also been shown to stabilize β-catenin by promoting its lactylation. This potentiates Wnt signaling and thereby fuels CRC cell proliferation [86]. Infection with human papillomavirus 16 (HPV16) is a major risk factor for cervical cancer. HPV E6 has been reported to promote glucose-6-phosphate dehydrogenase (G6PD) dimerization by suppressing its lactylation at Lys45, thereby enhancing G6PD activity and activating the pentose phosphate pathway (PPP). This metabolic rewiring supports cervical cancer cell proliferation [50]. AARS1 has been proposed to act as a lactate sensor that couples intracellular lactate to nuclear signaling. Upon sensing lactate, AARS1 promotes lactylation of YAP at Lys90, enhancing YAP–TEAD transcriptional activity downstream of Hippo signaling. Notably, AARS1 is itself a YAP–TEAD target gene, establishing a feedforward loop that sustains YAP output and promotes gastric cancer cell proliferation [24].

Fig. 2.

Lactylation promotes cancer cell proliferation. Lactate-driven lactylation of non-histone proteins (including YAP, G6PD, eEF1A2 and IGF1R) together with histone H3K18 lactylation, supports tumor-cell proliferation. Abbreviations: KCNK1, potassium two-pore domain channel subfamily K member 1; LDHA, lactate dehydrogenase A; HPV, human papillomavirus; AARS1, alanyl-tRNA synthetase 1; G6PD, glucose-6-phosphate dehydrogenase; YAP, Yes-associated protein; PPP, pentose phosphate pathway; eEF1A2, eukaryotic translation elongation factor 1 alpha 2; IGF1R, insulin-like growth factor 1 receptor

Invasion and metastasis

Tumor invasion and metastasis require dynamic remodeling of cell–matrix interactions and acquisition of migratory and invasive programming that enable dissemination. Invasive tumor cells often display metabolic rewiring, including enhanced aerobic glycolysis, which can drive nutrient competition, hypoxia and lactate accumulation within the TME. Lactate, a by-product of glycolysis, not only supports tumor cell proliferation but can also promote invasion and metastatic spread (Fig. 3). In head and neck squamous cell carcinoma, H3K18la has been shown to upregulate RRAS2, thereby promoting metastasis and therapy resistance [46]. In CRC, the long non-coding RNA USP3-AS1 stabilizes USP3 mRNA, thereby increasing expression of the deubiquitinating enzyme USP3 and promoting c-Myc deubiquitination. Stabilized c-Myc in turn augments glycolytic flux and lactate production, leading to elevated H3K18la and CDC27 upregulation, ultimately facilitating CRC liver metastasis [51]. In addition, the long non-coding RNA STEAP3-AS1 forms R-loops at its cognate locus, thereby upregulating the chromatin remodeling factor Brg1. Increased Brg1 promotes assembly of a Brg1–HDAC3–p300 complex and enhances H3K18la, which in turn potentiates ERG-dependent transcription of MMP9 and promotes CRC metastasis [109]. GPR37 has been reported to enhance glycolysis through Hippo–YAP pathway signaling, which increases H3K18la and upregulates the chemokines CXCL1 and CXCL5. This axis ultimately promotes CRC liver metastasis [110]. In bladder cancer, hypoxia-induced pyrroline-5-carboxylate reductase 1 (PYCR1) enhances glycolysis, increasing H3K18la and upregulating SLC6A14. This boosts glutamine metabolism and drives tumor growth and metastasis [63]. PYCR1 exerts a similar pro-metastatic effect in liver cancer. By enhancing glycolysis and activating PI3K–AKT–mTOR and MAPK–ERK signaling, PYCR1 increases H3K18la and upregulates IRS1, leading to liver cancer metastasis [55]. H3K18la can also upregulate VCAM1 and activate AKT–mTOR signaling, thereby promoting gastric cancer invasion and metastasis [43]. Incomplete microwave ablation is associated with unfavorable outcomes in hepatocellular carcinoma. Post-ablation lactate accumulation enhances H3K18la and increases transcription of NFS1 (cysteine desulfurase). Upregulated NFS1 promotes ferroptosis resistance, metastasis and oxaliplatin resistance in hepatocellular carcinoma cells. Conversely, pharmacological or genetic inhibition of NFS1 improves therapeutic responses [56]. KCNK1 binds to and activates LDHA, thereby promoting histone H3K18la and inducing expression of downstream targets, including ZWINT, ECT2, ANLN and EZR. This axis drives malignant progression in breast cancer [38]. Histone H3K9 is also a prevalent site of lactylation. In CRC, oncogenic KRAS mutations increase H3K9 lactylation (H3K9la), upregulating GRAMD1A and enhancing cholesterol metabolism. This axis drives CRC growth and metastatic progression [52].

Fig. 3.

Lactylation promotes cancer metastasis. Lactate-driven lactylation of non-histone proteins promotes tumor metastasis by enhancing tumor stemness, M2 macrophage polarization, pentose phosphate pathway activity, epithelial–mesenchymal transition, vascular mimicry and cytoskeletal remodeling. In addition, lactate-induced histone lactylation (notably H3K9 and H3K18) increases the expression of invasion- and migration-associated genes, thereby facilitating tumor-cell invasion and dissemination. Abbreviations: GPR37, G protein-coupled receptor 37; EGFR, epidermal growth factor receptor; PYCR1, pyrroline-5-carboxylate reductase 1; KCNK1, potassium two-pore domain channel subfamily K member 1; c-MYC, MYC proto-oncogene, bHLH transcription factor; USP3-AS1, USP3 antisense RNA 1; SOX9, SRY-box transcription factor 9; RIG-I, retinoic acid–inducible gene I (DDX58); DCBLD1, discoidin, CUB and LCCL domain-containing protein 1; YY1, Yin Yang 1; VEGFR2, vascular endothelial growth factor receptor 2 (KDR); VE-cadherin, vascular endothelial cadherin (CDH5); PRMT1, protein arginine methyltransferase 1

Beyond histones, lactylation of non-histone proteins can also shape tumor invasion and metastasis. SOX9, a highly conserved SRY-box transcription factor, is implicated in maintaining cancer stem-like traits, coordinating metabolic rewiring and promoting tumor cell proliferation and invasion [65]. In non-small cell lung cancer, hypoxia enhances glycolysis, increasing lactate production and promoting lactylation-dependent SOX9 expression. Elevated SOX9 reinforces stemness programming and drives tumor growth and metastasis [67]. Intratumoral bacteria are increasingly recognized as modulators of tumor biology. In CRC, Escherichia coli has been reported to elevate lactate production, triggering lactylation-dependent activation of retinoic acid-inducible gene I (RIG-I). Activated RIG-I suppresses NF-κB-driven NLRP3 transcription, promotes M2 macrophage polarization and thereby facilitates CRC liver metastasis [69]. In cervical cancer, lactate promotes lactylation of DCBLD1 at Lys172, stabilizing DCBLD1 and activating the G6PD-driven pentose phosphate pathway. This metabolic rewiring supports cervical cancer metastasis [70]. In gallbladder carcinoma, lactylation of YY1 at Lys183 activates FBXO33 transcription, thereby promoting polyubiquitination of p53 at Lys291 and Lys292. This facilitates epithelial–mesenchymal transition (EMT) and enhances invasive and metastatic potential [73]. In renal cell carcinoma, KAT8 and SIRT3 promote lactylation of malate dehydrogenase 2 (MDH2) at Lys239, enhancing MDH2 activity and strengthening its interaction with the citrate transporter SLC25A1. This increases citrate export and boosts IDH1-dependent NADPH and NADH production, thereby facilitating metastasis [92]. Hypoxia enhances glycolysis and elevates lactate, which drives lactylation of YTHDC1 at Lys82 and promotes its phase separation. Phase-separated YTHDC1 stabilizes transcripts such as BCL2 and E2F2, thereby promoting invasion and metastasis [74]. In addition, hypoxia also induces PRMT1 lactylation at Lys134 and Lys145, enhancing its catalytic activity and promoting asymmetric dimethylation of vimentin at Arg64. This modification drives cytoskeletal remodeling and facilitates tumor cell metastasis [78]. Extracellular lactate has been reported to enter cells and promote p300-dependent lactylation of Rab7A. Rab7A lactylation attenuates its GTPase activity and facilitates trafficking of multivesicular bodies (MVBs) to the plasma membrane. Consequently, tumor-derived exosome secretion increases, promoting liver cancer metastasis [96]. LDHA binds to and promotes lactylation of vascular endothelial growth factor receptor 2 (VEGFR2) and VE-cadherin, increasing their protein abundance. As markers of vascular mimicry (VM), VEGFR2 and VE-cadherin support glioblastoma cell proliferation, migration and invasion [101].

Angiogenesis

Blood vessels deliver oxygen and nutrients and remove metabolic waste, and are therefore essential for highly metabolically active tumors. Tumor neovascularization occurs mainly through two routes. The predominant route is endothelial angiogenesis, in which functional vessels are formed by endothelial cells. By contrast, some tumors generate endothelial-like tubular networks composed largely of tumor cells; this phenomenon, termed vascular mimicry (VM), represents a tumor-specific vascular pattern. Tumor angiogenesis is a key driver of rapid tumor expansion and metastatic dissemination, and emerging evidence implicates lactylation as an important regulator of this process (Fig. 4).

Fig. 4.

The role of lactylation in cancer angiogenesis. Lactate-driven lactylation of ASH2L, YY1, HIF-1α and histone H3 promotes tumor angiogenesis by activating the expression of downstream pro-angiogenic targets. Abbreviations: DNMT3A, DNA methyltransferase 3 A, ST2, suppression of tumorigenicity 2; GP73, Golgi Protein 73; GRP78, Glucose-Regulated Protein 78, ASH2L, Set1/Ash2 histone methyltransferase complex subunit; YY1, Yin Yang 1; FGF2, fibroblast growth factor 2; LDHA, lactate dehydrogenase A; HIF-1α, hypoxia and hypoxia-inducible factor-1alpha; VEGFR2, vascular endothelial growth factor receptor 2; VE-cadherin, vascular endothelial cadherin

Vascular endothelial growth factor (VEGF) is a central pro-angiogenic factor in tumors. DNMT3A has been reported to promote angiogenesis by enhancing HIF-1α lactylation, at least in part by facilitating lactate trafficking to the nucleus. Lactylated HIF-1α in turn increases VEGF expression, thereby stimulating angiogenic responses in endothelial cells [111]. In prostate cancer, hypoxia-induced HIF-1α enhances glycolytic flux, leading to lactate accumulation. Lactate-dependent lactylation of HIF-1α has been reported to further potentiate its transcriptional activity, thereby inducing KIAA1199 while repressing Sema3A. Which also increases the expression of pro-angiogenic and VM–associated factors, including VEGF and VE-cadherin, ultimately promoting tumor angiogenesis and VM [104]. Accordingly, targeting HIF-1α lactylation—such as by inhibiting monocarboxylate transporter 1 (MCT1) or the downstream effector KIAA1199—may provide a rational adjunct to anti-angiogenic therapy in prostate cancer [104]. In glioma cells, p300-mediated lactylation of YY1 at Lys183 enhances YY1 transcriptional activity, thereby inducing FGF2 expression and promoting angiogenesis [79]. Histone H3K9la has also been implicated in tumor angiogenesis. Lactate-driven H3K9la suppresses HDAC2 expression, activates angiogenesis-associated gene expression and promotes vessel formation. Conversely, HDAC2 dampens H3K9la and restrains angiogenesis. Together, these opposing activities establish a negative-feedback circuit that maintains dynamic homeostasis [84]. In melanoma, lactate-driven histone lactylation augments IL-33–ST2 signaling and promotes angiogenesis. Accordingly, combining anti-angiogenic therapy with an ST2 inhibitor markedly suppresses melanoma growth [64]. In hepatocellular carcinoma, lactylation of ASH2L at Lys312 within the Set1/Ash2 histone methyltransferase complex has been reported to promote angiogenesis. Mechanistically, ASH2L(K312) lactylation enriches across the VEGFA coding region and facilitates enhancer–promoter communication, thereby boosting VEGFA transcription and driving tumor vascularization [97]. In hepatocellular carcinoma, lactate-driven histone lactylation has been reported to upregulate GP73, thereby promoting STAT3 phosphorylation and exacerbating GRP78-associated endoplasmic reticulum stress. This signaling cascade increases the expression of angiogenesis-related mediators and ultimately enhances angiogenesis [112]. In glioma, the pseudogene MAPK6P4 has been reported to encode a micropeptide with kinase activity that promotes KLF15 phosphorylation, thereby facilitating its nuclear translocation and inducing LDHA transcription. LDHA in turn binds to VEGFR2 and VE-cadherin and enhances their lactylation, increasing protein stability and ultimately promoting angiogenesis and VM [101].

Immune evasion

Tumor immune evasion describes the ability of tumor cells to avoid immune recognition and destruction by rewiring immune-regulatory pathways and remodeling the TME. This enables persistent tumor growth and metastatic dissemination [85]. Metabolic reprogramming is a hallmark mechanism that supports tumor immune evasion. By reshaping nutrient availability and metabolite cues within the TME, tumor cells can rewire antitumor immunity and thereby fuel disease progression. Recent studies further implicate lactate as a key immunoregulatory metabolite, acting in part through protein lactylation (Fig. 5).

Fig. 5.

Lactylation contributes to cancer immune evasion. In tumors, protein lactylation can foster immune escape by reshaping anti-tumor immunity, including dampening effector T cell function and promoting T cell exhaustion, activating tolerogenic myeloid programming, and enhancing regulatory T cell (Treg) activity. Abbreviations: PRMT3, protein arginine methyltransferase 3; PDHK1, pyruvate dehydrogenase kinase 1; METTL3, methyltransferase-like 3; JAK1, Janus kinase 1; STAT3, signal transducer and activator of transcription 3; POM121, pore membrane protein 121; PD-L1, programmed death-ligand 1 (CD274); Nur77, nuclear receptor subfamily 4 group A member 1 (NR4A1); Tonic TCR, tonic T cell receptor signaling; ENSA, endosulfine alpha; PP2A, protein phosphatase 2 A; CCL2, C–C motif chemokine ligand 2; PLAU, plasminogen activator, urokinase; IL11, interleukin 11; moesin, moesin (MSN); TGF-β, transforming growth factor beta; SMAD3, SMAD family member 3; APOC2, apolipoprotein C-II; RIG-I, retinoic acid–inducible gene I (DDX58); NF-κB, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3

In hepatocellular carcinoma, PRMT3 has been reported to interact with pyruvate dehydrogenase kinase 1 (PDHK1), promoting demethylation at Arg363 and Arg368 and increasing PDHK1 kinase activity, thereby enhancing lactate production. PRMT3–PDHK1 signaling has further been linked to elevated histone H3K18la, which upregulates PD-L1 expression and promotes immune evasion in hepatocellular carcinoma cells [57]. CD8⁺ T cells are principal cytotoxic effectors in antitumor immunity. Their activation and intratumoral infiltration are hallmarks of effective immune surveillance, whereas functional suppression promotes tumor immune evasion [89]. In oral squamous cell carcinoma, endogenous retrovirus group E member 1 (EVA1A) is upregulated and inversely correlated with CD8⁺ T cell infiltration. Mechanistically, EVA1A enhances glycolysis and lactate export, which is associated with increased histone H4K12 lactylation and induction of PLAU expression. This axis blunts CD8⁺ T cell activation and promotes immune evasion in oral squamous cell carcinoma [66]. Cohort studies in small cell lung cancer have linked elevated lactate dehydrogenase (LDH) levels to poor outcomes in patients receiving immunotherapy. Mechanistically, high LDH activity promotes lactate accumulation, which drives histone H3K18la. This epigenetic programming induces Nur77 expression in naïve CD8⁺ T cells, enforcing tonic TCR signaling that blunts antigen sensing and undermines antitumor effector function. Consistently, pharmacological inhibition of lactate production or export can enhance responses to anti-PD-1 therapy [68]. In non-small cell lung cancer, H3K18la has been reported to induce pore membrane protein 121 (POM121) transcription, thereby sustaining c-Myc signaling and increasing PD-L1 expression, which collectively promotes immune evasion. Consistently, combining glycolysis inhibition with anti-PD-1 blockade yields improved therapeutic responses [71]. Glycolysis-driven H3K18la has been reported to induce B7-H3 expression by increasing B7-H3 promoter accessibility and facilitating CREB1–EP300 engagement, resulting in CD8⁺ T-cell infiltration and cytotoxic capacity. Accordingly, dual targeting of glycolysis and B7-H3 can suppress tumor growth [72]. In CRC, KRAS-mutant tumor cells generate lactate that promotes histone H3K18la and induces circATXN7 transcription. circATXN7 directly binds the NF-κB p65 subunit, masks its nuclear localization signal and sequesters it in the cytoplasm. This pathway promotes tumor immune evasion by increasing the susceptibility of tumor-specific cytotoxic T lymphocytes (CTLs) to activation-induced cell death (AICD) [53]. Tumor-infiltrating myeloid cells (TIMs) are also key mediators of immune evasion. Lactate-driven H3K18la has been reported to induce METTL3 expression, which in turn enhances N6-methyladenosine (m6A) modification of JAK1 mRNA and promotes JAK1 translation. Increased JAK1 abundance activates STAT3 signaling, thereby fostering an immunosuppressive TIM programming and facilitating tumor immune evasion [47]. Histone lactylation is not limited to H3K18 and H4K12. In head and neck squamous cell carcinoma, H3K9la in CD8⁺ T cells has been linked to IL-11 induction and subsequent activation of JAK2–STAT3 signaling. This axis promotes CD8⁺ T cell exhaustion and facilitates tumor immune evasion [48]. In glioma, epidermal growth factor receptor (EGFR) activation engages ERK signaling, which phosphorylates acetyl-CoA synthetase 2 (ACSS2) and promotes its nuclear translocation to interact with lysine acetyltransferase 2 A (KAT2A). In the nucleus, ACSS2 functions as a lactyl-CoA synthetase to generate lactyl-CoA, which is then transferred to histone H3 by KAT2A. Histone H3 lactylation in turn activates Wnt/β-catenin and NF-κB signaling and increases PD-L1 expression, thereby promoting glioma growth and immune evasion. Consistently, co-treatment with an ACSS2–KAT2A complex inhibitor and anti-PD-1 blockade suppresses tumor growth, supporting a key role for histone lactylation in glioma immune evasion [75].

Beyond histone lactylation, non-histone lactylation also contributes to tumor immune evasion. In regulatory T cells (Tregs), lactate-driven lactylation of MOESIN at Lys72 enhances its interaction with TGF-β receptor I and activates SMAD3 signaling, thereby augmenting Treg suppressive function. Consistently, combining lactate dehydrogenase inhibition with anti-PD-1 blockade is more effective than anti-PD-1 monotherapy [95]. Lactate also promotes lactylation of APOC2 at Lys70, increasing APOC2 stability. This is proposed to enhance free-fatty-acid release, drive Tregs accumulation and establish an immunosuppressive microenvironment. Conversely, an APOC2^K70la targeting antibody sensitizes tumors to anti-PD-1 immunotherapy [80]. Metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC) fosters an immunosuppressive TME characterized by elevated lactate, thereby promoting immune evasion and therapeutic resistance. Non-histone lactylation of ENSA at Lys63 has been identified as a key regulator of this axis: ENSA^K63la inhibits PP2A and activates STAT3–CCL2 signaling, driving tumor-associated macrophage (TAM) recruitment and suppressing cytotoxic T-cell function [106]. In macrophages, Escherichia coli has been reported to induce lactylation of RIG-I, which limits NF-κB recruitment to the NLRP3 promoter and thereby suppresses NLRP3 transcription. In CRC, NLRP3 deficiency compromises the immunosuppressive activity of Tregs and the antitumor function of CD8⁺ T cells, ultimately promoting liver metastasis [69].

Radiation resistance

Radiotherapy is a cornerstone of cancer treatment and can achieve durable tumor control in a wide range of malignancies. Radiotherapy exerts its antitumor effects primarily by inducing DNA damage through ionizing radiation, thereby triggering tumor-cell death. However, altered DNA-damage repair capacity, antioxidant defenses, metabolic reprogramming and cancer stem-like states can confer radioresistance and limit therapeutic efficacy. Emerging evidence further implicates protein lactylation in radiotherapy resistance (Fig. 6).

Fig. 6.

Lactylation contributes to cancer radioresistance. In tumor cells, protein lactylation may promote resistance to radiotherapy by reinforcing stem-like programming and enhancing DNA-damage repair capacity. Abbreviations: AMPK, AMP-activated protein kinase; GOLPH3, Golgi phosphoprotein 3; ALDH1A3, aldehyde dehydrogenase 1 family member A3; USP4, ubiquitin-specific peptidase 4; MCM7, minichromosome maintenance complex component 7; BMX, BMX non-receptor tyrosine kinase; MRE11, MRE11 homolog, double-strand break repair nuclease (MRE11A); PPA1, inorganic pyrophosphatase 1

Glioblastoma stem-like cells are a major determinant of glioma radioresistance, yet the underlying mechanisms remain incompletely understood. Histone H3K18la has been reported to upregulate the deubiquitinase USP4, thereby sustaining the stem-like state of glioblastoma stem cells. Mechanistically, USP4 binds ANXA2 and limits its ubiquitin-dependent degradation, leading to ANXA2 accumulation. Elevated ANXA2 activates BMX–STAT3 signaling to maintain glioblastoma stemness and enhance resistance to radiotherapy [76]. Similarly, in hepatocellular carcinoma, glycolysis-driven histone lactylation has been linked to upregulation of minichromosome maintenance complex component 7 (MCM7), thereby sustaining stem-like traits and promoting radioresistance [58]. In CRC, Golgi phosphoprotein 3 (GOLPH3) promotes AMPK-dependent glycolysis by facilitating Smoothened (SMO) assembly at the plasma membrane, thereby enhancing tumor-cell growth, migration and radioresistance. Reciprocally, glycolysis-driven histone H3K18la at the GOLPH3 promoter increases GOLPH3 transcription, establishing a positive-feedback circuit that amplifies malignant progression [54]. Radiotherapy kills tumor cells largely by inducing DNA damage; accordingly, the capacity to repair such lesions is a major determinant of resistance to radiation-induced cell death. In lung adenocarcinoma, global protein lactylation is elevated, and multiple components of the non-homologous end-joining (NHEJ) pathway—including Ku70 and Ku80—have been reported to undergo lactylation. Inhibition of lactylation impairs NHEJ efficiency [81]. MRE11 is a core component of the DNA double-strand break (DSB) repair machinery, and lactylation at Lys673 has been reported to enhance its repair activity. In triple-negative breast cancer, lactate-driven MRE11^K673lac has been implicated as a determinant of radioresistance [93]. Saikosaponin D enhances the response of triple-negative breast cancer to radiotherapy by increasing radiosensitivity and inducing HIF-1α-dependent HDAC5 expression. HDAC5 then removes lactylation from MRE11 at Lys673, thereby dampening MRE11-mediated DNA repair and sensitizing tumor cells to ionizing radiation [103]. Collectively, these findings suggest that lactylation of DNA-repair proteins may represent an underappreciated driver of radioresistance. Moreover, lactylation of regulatory factors that govern DNA-damage responses can further modulate radiotherapy resistance. HAT1 has been proposed to function as a lactyltransferase, and lactylation at Lys15 enhances its enzymatic activity [105]. Activated HAT1 promotes RPA1 lactylation, thereby augmenting homologous recombination repair and increasing radioresistance. Lactylated RPA1 exhibits enhanced binding to single-stranded DNA and the MRE11–RAD50–NBS1 (MRN) complex, further strengthening DNA repair capacity and radiation tolerance in lung adenocarcinoma. Consistently, HAT1 depletion sensitizes lung adenocarcinoma cells to radiotherapy [82]. In glioma stem-like cells, ALDH1A3 interacts with PKM2 to promote PKM2 tetramerisation, thereby enhancing glycolytic flux and driving lactate accumulation. Elevated lactate in turn induces XRCC1 lactylation at Lys247. XRCC1^K247la facilitates its nuclear accumulation, where it supports DNA repair and ultimately confers radioresistance [102]. Whether additional DNA-repair factors are subject to lactylation, and how such modifications shape repair pathway choice and efficiency, remains largely unexplored and warrants further investigation.

Systemic therapy resistance

Drug-based killing of tumor cells remains a mainstay of contemporary cancer therapy. Whether administered as an adjuvant after surgery or as a first-line option, chemotherapy, targeted therapies and immunotherapies are indispensable components of cancer management. However, a subset of patients exhibited either primary (intrinsic) resistance or acquire resistance during treatment, leading to rapid disease progression and poor clinical outcomes. Overcoming therapeutic resistance therefore remains a major bottleneck in cancer care [113]. Lactate accumulation is a defining feature of many tumors. Emerging evidence links lactate-driven protein lactylation to resistance to systemic therapies, including chemotherapy, targeted therapy and immunotherapy (Table 4).

Table 4.

Lactylation in resistance to systemic therapies

Lactylation Targets	Modification site	Downstream targets	Mechanism	Drug resistence	Reference
H3	K18	YBX1↑,YY1↑	DNA damage repair↑	Cisplatin resistence	[114, 115]
XRCC1	K247	/	DNA damage repair↑	Temozolomide resistance	[93, 102]
H3	K18	BUBCNL↑, Pacer↑	Autophage↑	Bevacizumab resistance	[116, 117]
H3	K9	LUC7L2↑, MLH1↓	mismatch repair↓	Temozolomide resistance	[74, 77]
IGF2BP3	K76	PCK2↑,NFR2↑	Antioxidant activity↑	Lenvatinib	[98, 106]
IGF2BP3	K76	FSP1↑	Ferroptosis↓	Oxaliplatin	[76, 99]
ENSA	K63	STAT3↑,CCL2↑	Immune inhibition↑	Immune therapy	[118, 119]
H3	K18	GCH↑,FTH↑	Ferroptosis↓	Doxorubicin	[38, 40]
METTL3	K27	WTAP	DNA repair↓	Cisplatin	[75, 94]
XLF	K288	/	Homologous recombination repair↑	5-FU	[87, 112]
H3	K14	NEDD4↑, PTEN↓	Anti-apoptosis↑, stress resistance↑	5-FU	[59, 110]
PRDX	K67	Nfr2	Ferroptosis↓	Regorafenib	[58, 100]
H3	K18	HECTD2, KEAP	Antioxidant activity↑	Lenvatinib	[60, 63]
H3	K9	RAD51↑, BRCA2↑	Homologous recombination repair↑	Cisplatin	[82, 107]
RAD51	K73	/	Homologous recombination repair↑	Cisplatin	[82, 107]
H3	K12	MYC↑, RAD23A↑	DNA damage repair↑	Niraparib	[41, 42]
NSUN2	K508	GCLC↑	Ferroptosis↓	Doxorubicin	[66, 90]
GCLM	K34	/	Ferroptosis↓	Erastin	[88, 120]
ROCK1	K13	DRP↓	Fragmented mitochondria↑	Immune therapy	[108, 118]
ANTXR	K453	RhoC/ROCK/SMAD5↑	Stemness↑	Oxaliplatin	[85, 88]
BLM	K24	RAD51↑	Homologous end-joining repair↑	Anthracyclines	[102, 108]
PCBP2	K115	PCBP2↑	Ferroptosis↓	Oxaliplatin	[68, 91]
H3	K14	LDHA↑, PCBP2↑	Ferroptosis↓	Oxaliplatin	[68, 91]
Mic60	K282	EGFR↑	mitochondrial metabolism↑	TKI	[79, 83]

↑ up regulation, ↓ down regulation

Studies in bladder cancer have linked enhanced glycolysis to cisplatin resistance. Mechanistically, glycolysis-driven H3K18la has been reported to induce YBX1 and YY1 expression, thereby promoting cisplatin resistance in bladder cancer cells [115]. ALDH1A3 has been implicated in the poor prognosis of glioma. It interacts with PKM2 to promote PKM2 tetramerization, thereby enhancing glycolytic flux and driving lactate accumulation. Elevated lactate in turn induces XRCC1 lactylation at Lys247. XRCC1^K247la facilitates nuclear accumulation and supports DNA repair, ultimately conferring resistance to Temozolomide [102]. H3K18la has also been reported to induce transcription of RUBCNL /Pacer and to strengthen Pacer–BECN1 (Beclin 1) association, thereby promoting recruitment and activity of the class III phosphatidylinositol 3-kinase (PI3K) complex. This accelerates autophagosome maturation, supporting CRC cell survival under hypoxia and promoting resistance to bevacizumab [117]. Lactate accumulation increases H3K9la and upregulates LUC7L2 expression. Elevated LUC7L2 promotes retention of exon 7 in MLH1 transcripts, leading to reduced MLH1 expression. Consequently, DNA mismatch repair is compromised, conferring temozolomide resistance in glioblastoma cells [77]. In hepatocellular carcinoma, lactylation of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) has been reported to enhance its activity and increase expression of downstream targets, including mitochondria phosphoenolpyruvate carboxykinase 2 (PCK2) and nuclear factor erythroid 2-related factor 2 (NRF2). This rewires serine metabolism and strengthens antioxidant defenses, thereby promoting lenvatinib resistance [98]. IGF2BP3^K76la has also been reported to increase its binding to FSP1 mRNA, thereby elevating FSP1 protein abundance and suppressing ferroptosis. This axis ultimately promotes resistance to platinum-based chemotherapy in hepatocellular carcinoma cells [99]. In PDAC, lactate-driven lactylation of endosulfine-α (ENSA) at Lys63 has been linked to activation of the STAT3–CCL2 axis. This promotes an immunosuppressive TME and contributes to resistance to immunotherapy [119]. In triple-negative breast cancer, lactate released by tumor-associated fibroblasts has been reported to promote doxorubicin resistance. Mechanistically, lactate-driven histone lactylation increases ZFP64 expression, which in turn induces downstream effectors, including GCH and FTH. This programme suppresses ferroptosis and ultimately confers doxorubicin resistance [40]. HDAC2 promotes delactylation of METTL3, thereby strengthening its interaction with Wilms tumor 1-associating protein (WTAP) and increasing the abundance of downstream effectors. This enhances DNA repair capacity and ultimately promotes cisplatin resistance in triple-negative breast cancer [94]. Glycolysis-derived lactate has also been reported to promote lactylation of XLF at Lys288, thereby enhancing homologous recombination repair and conferring chemotherapy resistance in CRC [87]. H3K14la has been reported to induce expression of the E3 ubiquitin ligase NEDD4, which promotes ubiquitin-dependent degradation of the tumor suppressor PTEN. Loss of PTEN further accelerates glycolysis, reinforcing H3K14la and establishing a positive-feedback circuit. This loop ultimately promotes 5-fluorouracil (5-FU) resistance in liver cancer cells [59]. ZNF207 has also been reported to enhance cellular antioxidant capacity by promoting lactylation of peroxiredoxin 1 (PRDX1) at Lys67, which facilitates PRDX1 nuclear translocation and induces downstream NRF2 expression. This axis suppresses ferroptosis and ultimately promotes regorafenib resistance in liver cancer cells [100]. H3K18la induces HECTD2 expression, promoting degradation of the downstream target KEAP1. This enhances antioxidant signaling and ultimately promotes lenvatinib resistance in hepatocellular carcinoma [60]. Histone lactylation can also increases major vault protein (MVP) expression, thereby strengthening MVP–β-transducin repeat-containing protein (β-TrCP) interaction. This limits β-TrCP–mediated PD-L1 degradation, stabilizing PD-L1 and promoting immunotherapy resistance in hepatocellular carcinoma [61]. In ovarian cancer, H3K9la induces RAD51 and BRCA2 expression, thereby enhancing homologous recombination repair. In parallel, lactate promotes RAD51 lactylation at Lys73, potentiating RAD51 activity and fostering cisplatin resistance [107]. Additionally, H3K12 lactylation promotes DNA repair by inducing MYC expression and upregulating the downstream effector RAD23A, thereby conferring niraparib resistance in ovarian cancer cells [42]. Lactylation of NSUN2 at Lys508 increases its catalytic activity and enhances m5C deposition on GCLC mRNA. This stabilizes GCLC transcripts, boosts glutathione metabolism and suppresses ferroptosis, thereby promoting doxorubicin resistance in gastric cancer cells [90]. GCLM can also undergo ACAT2-mediated lactylation, which increases intracellular glutathione levels, suppresses ferroptosis and promotes chemoresistance [120]. The TME is a key determinant of therapy resistance, owing in part to its ability to remodel tumor-cell states and the oxidative milieu. Conversely, lactate produced by tumor metabolic reprogramming can further reshape the TME [114, 116]. Lactate accumulation in the TME can inactivate natural killer (NK) cells, thereby undermining NK cell–based immunotherapy. Mechanistically, elevated lactate increases intracellular protein lactylation in NK cells, perturbs nicotinamide adenine dinucleotide (NAD) metabolism and drives mitochondrial fragmentation, resulting in reduced cytotoxicity. One proposed route involves lactylation of ROCK, which dampens ROCK–DRP signaling and promotes mitochondrial fragmentation, ultimately compromising NK-cell function [118]. In CRC, lactylation of ANTXR at Lys453 increases protein stability, activates RhoC–ROCK–SMAD5 signaling and promotes cancer stem-like traits, thereby enhancing oxaliplatin resistance [88]. AARS1, a recently identified lactyltransferase, recognizes BLM and catalyzes its lactylation at Lys24. BLM^K24la enhances BLM stability by suppressing MIB1-mediated ubiquitination, thereby strengthening its association with DNA-repair factors and promoting DNA end resection and homologous recombination repair. This ultimately fosters resistance to DNA-damaging chemotherapy [108]. In oral squamous cell carcinoma, histone deacetylation increases BCAM expression, thereby promoting cisplatin resistance [121]. LncRNAs are key regulators of cellular progression and can contribute to lactate-associated chemoresistance. In gastric cancer, BASP1-AS1 acts as a scaffold that bridges ULK and LDHA, enhances glycolytic flux and promotes PCBP2 lactylation at Lys115. PCBP2^K115la weakens ARIH2–PCBP2 interaction, reducing ARIH2-mediated ubiquitination and thereby stabilizing PCBP2. In parallel, BASP1-AS1 increases LDHA and PCBP2 transcription by promoting H3K14la, reinforcing ferroptosis suppression and ultimately conferring oxaliplatin resistance [91]. In lung cancer, Mic60 lactylation drives metabolic reprogramming and thereby promotes resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) [83]. Although evidence linking protein lactylation to resistance to systemic therapies remains limited, an expanding body of work supports a substantive role for this modification in drug resistance.

Application of targeted protein lactylation in cancer therapy

Lactylation functions as a lactate-derived metabolic signaling mechanism that couples cellular metabolic status to transcriptional regulation and protein function, thereby contributing to immune homeostasis, inflammation resolution, tissue repair, cell fate determination and metabolic adaptation [8, 122–125]. Protein lactylation has emerged as an important regulator of tumor initiation and growth, highlighting this modification as a potential therapeutic vulnerability. Because lactate provides the acyl donor for lactylation, intracellular lactate availability is a major determinant of lactylation dynamics. Accordingly, strategies to suppress lactylation include targeting glycolytic enzymes that fuel lactate production and monocarboxylate transporters that mediate lactate flux (Table 5). 2-Deoxy-D-glucose (2-DG) is a synthetic glucose analogue that competitively inhibits hexokinase 2 (HK2), thereby suppressing glycolysis and lactate production [134]. 2-DG reduces lactate production in preclinical models—including lung and endometrial cancer—thereby lowering intracellular lactate availability and restraining tumor growth. However, clinical translation has been limited, which may in part reflect unfavorable pharmacokinetics, including a short plasma half-life [126]. Fargesin, a lignan isolated from Magnolia species, suppresses tumor glycolysis by targeting the key glycolytic enzyme PKM2, thereby reducing lactate production. It concomitantly attenuates histone H3 lactylation and restrains tumor growth [127]. In glioma, dexmedetomidine suppresses glycolysis and reduces c-Myc lactylation, thereby limiting metastatic potential [128]. Stiripentol, a small-molecule inhibitor of LDHA, suppresses NBS1 lactylation and disrupts assembly of the MRN complex. This impairs DNA repair capacity and consequently sensitizes tumor cells to chemotherapy [129]. Royal jelly acid (RJA), a natural product, shows anti-tumor activity in liver cancer models, suppressing proliferation and migration while promoting apoptosis. Mechanistically, RJA reprograms cellular metabolism to reduce histone H3K9 and H3K14 lactylation [62]. Similarly, demethylzeylasteral (DML), a triterpene anticancer compound, suppresses liver cancer stem-cell (LCSC) tumorigenicity by attenuating H3K9 and H3K56 lactylation, two marks linked to metabolic stress [130]. Evodiamine, an alkaloid isolated from Evodia fruits, suppresses HIF1A expression and modulates histone H3K18la, thereby inhibiting Sema3A-driven angiogenesis and reducing PD-L1 expression in prostate cancer cells. Consequently, evodiamine increases tumor sensitivity to anti-angiogenic therapy and immunotherapy [131]. AZD3965 is a first-in-class inhibitor of MCT1 that is being evaluated in early-phase clinical studies. By blocking lactate transport, AZD3965 can dampen lactylation-dependent programming and the expression of downstream genes in tumors [135].

Table 5.

Therapeutic applications of lactylation-targeting strategies in cancer

Cancer type	Compound	Target	Mechanism	Outcome	Reference
Endometrial carcinoma	2-Deoxy-D-glucose (2DG)	HK2	Suppresses protein lactylation	Inhibits tumor growth	[126]
Non-small cell lung cancer	Fargesin	PKM2	Reduces histone H3 lactylation	Inhibits tumor growth	[127]
Glioma	Dexmedetomidine	Glycolysis	Reduces c-Myc lactylation	Inhibits tumor metastasis	[128]
Gastric cancer	Stiripentol	LDHA	Reduces NBS1 lactylation	Enhances chemosensitivity	[129]
Liver cancer	Royal jelly acid	Glycolysis	Reduces H3K9 and H3K14 lactylation	Inhibits tumor metastasis	[62]
Liver cancer	Demethylzeylasteral	Glycolysis	Reduces H3K9 and H3K56 lactylation	Suppresses tumorigenesis	[130]
Prostate cancer	Evodiamine	Sema3A	Reduces H3K18 lactylation	Sensitizes to anti-angiogenic therapy and immunotherapy	[131]
Liver cancer	Honokiol	SIRT3	Reduces CCNE2 lactylation	Induces apoptosis in hepatocellular carcinoma cells	[132, 133]
Triple-negative breast cancer	Saikosaponin D	HDAC5	Promotes MRE11 delactylation	Suppresses MRE11-dependent homologous recombination and increases radiosensitivity	[42, 103]
Colorectal cancer	AJ-64,234,603,004	RIG-I	Inhibits RIG-I lactylation	Blocks M2 macrophage polarization and sensitizes metastatic CRC to 5-FU–based chemotherapy	[69, 97]

Writers and erasers of Kla provide tractable entry points for therapeutic intervention. SIRT3, a class III deacetylase, also exhibits delactylase activity [132]. In hepatocellular carcinoma, honokiol activates SIRT3 and reduces lactylation of cyclin E2 (CCNE2), thereby promoting tumor-cell apoptosis and restraining malignant progression [133]. Saikosaponin D is a compound with anti-inflammatory, antiviral and anti-tumor properties [136]. A study has shown that Saikosaponin D increases HDAC5 expression, promotes de-lactylation of MRE11 and attenuates MRE11-dependent DNA recombination repair, ultimately enhancing radiosensitivity in triple-negative breast cancer [103]. Beyond modulating lactylation enzymes, directly targeting specific lactylation events represents an additional therapeutic strategy. A small-molecule inhibitor of RIG-I lactylation, AJ-64,234,603,004 ([7-(carboxymethyl)-10-methyl-10 H-phenothiazin-2-yl] acetic acid), suppresses RIG-I K852 lactylation, inhibits M2 macrophage polarization and sensitizes metastatic CRC to 5-FU-based chemotherapy [69].

However, current evidence suggests that targeting glucose metabolism or lactate-driven modifications alone is unlikely to deliver durable antitumor benefit. By contrast, combining glycolysis inhibitors—which also reduce lactate production—with other anticancer agents can yield superior therapeutic efficacy. To date, no MCT inhibitors have been approved for clinical use. AZD3965 is being evaluated in clinical trials, particularly in solid tumors with low MCT4 expression. Nevertheless, owing to compensatory lactate transport via alternative MCT family members, inhibiting a single MCT isoform may be insufficient, whereas rational combinations can produce meaningful benefit. For example, combining AZD3965 with a PD-L1 antibody–drug conjugate (PD-L1–ADC) can resensitize immunotherapy-refractory tumors to checkpoint blockade, promote immune infiltration and thereby convert “cold” tumors into “hot” tumors [137]. Similarly, co-targeting MCT4 and immune checkpoints improves therapeutic responses in CRC [138], with analogous findings reported in lung, liver and breast cancers and glioma [68, 71, 75, 95, 137]. Collectively, these data support the concept that pairing lactylation- or lactate-axis inhibitors with established anticancer therapies may represent a promising strategy. Notably, agents that selectively target lactylation itself remain scarce, probably owing to the relatively recent recognition of this modification and the limited specificity of current strategies, which mainly target glycolysis-related enzymes or lactylated proteins. Moreover, lactate metabolism and lactylation are not tumor-specific, raising the possibility that their inhibition may also affect normal cells. As the mechanisms underlying lactylation become increasingly defined, these challenges may be overcome, ultimately facilitating the clinical translation of therapeutic strategies that selectively target lactylation of specific proteins.

Discussion and perspectives

As an emerging post-translational modification, Kla is increasingly recognized as a regulator of diverse physiological and pathological programming. From a metabolic perspective, lactylation can be viewed as a conduit linking intracellular metabolic state to signal transduction. When cellular energy metabolism is heightened and lactate production rises, protein lactylation increases accordingly, rapidly relaying metabolic cues to signaling pathways and reshaping cellular behavior. Here, we outline the biogenesis of protein lactylation and synthesize current evidence for its roles in tumor growth, invasion and metastasis, angiogenesis, immune evasion, and resistance to radiotherapy and systemic therapies, with an emphasis on underlying molecular mechanisms. We highlight lactate accumulation as a major determinant of lactylation, driven largely by dysregulated aerobic glycolysis and altered lactate transport. Accordingly, targeting glycolysis or monocarboxylate transporter activity can reduce intracellular lactylation.

Decades of work have established that many tumors preferentially rely on aerobic glycolysis for glucose utilization and energy production, even in the presence of oxygen [139]. This metabolic programming implies substantial lactate accumulation within tumors. Although high extracellular lactate can be cytotoxic in many contexts, intratumoral lactate concentrations have been reported to reach 10–30 mM, and can be even higher. Notably, tumor cells often remain viable despite this pronounced lactate burden [10]. These observations suggest that lactate is not merely a toxic by-product but can actively support tumor progression. Lactate has been implicated in promoting tumor growth, invasion and metastasis, rewiring immune-cell metabolism and fostering an immunosuppressive microenvironment that enables immune evasion [140]. Subsequent work has shown that tumor cells can import and metabolize lactate as a carbon source to fuel malignant growth and metastatic dissemination. Lactate can also modulate intracellular signaling networks in ways that favor tumor progression, although the underlying mechanisms have remained incompletely defined. The identification of Kla in 2019 provided a mechanistic framework for how lactate-derived cues can be translated into changes in protein function and gene regulation, opening a new chapter in our understanding of lactate signaling [8]. Emerging evidence suggests that lactate can influence protein activity by being converted into activated acyl donors, such as lactyl-CoA, thereby enabling Kla. Lactylation can be installed by dedicated writer enzymes and, in some contexts, may also be shaped by lactate-sensing pathways that reprogramed cellular metabolism and chromatin states. By altering protein function and gene expression, lactylation engages signaling circuits that support malignant progression. Together, these insights refine the long-standing view that lactate-rich TMEs are pro-tumorigenic and highlight therapeutic opportunities along the lactate–lactylation axis [8]. Resistance to radiotherapy and systemic therapies remains a major obstacle in cancer treatment, in part because tumors can reprogramme their metabolism to acquire therapy resistance [21]. For DNA-damaging therapies, metabolically produced lactate can promote transcriptional programming that enhance DNA repair capacity, thereby fostering resistance to radiotherapy and systemic therapies [6, 129]. Immunotherapy has transformed cancer treatment by harnessing the immune system to eliminate malignant cells, yet clinical benefit remains limited in many solid tumors. One contributing factor is lactate accumulation within tumors, which helps establish an immunosuppressive microenvironment. At the molecular level, lactate-driven lactylation can induce expression of immune checkpoint molecules such as PD-L1, thereby diminishing the efficacy of PD-L1–targeted therapies [57, 141]. However, monotherapy with glycolysis-targeting agents has shown limited clinical benefit and is often hampered by dose-limiting toxicities, including gastrointestinal adverse events and neurotoxicity [126, 134]. These observations underscore the limitations of single-agent therapy and support the need for rational combination strategies to achieve durable anti-tumor efficacy. Bevacizumab, a widely used anti-angiogenic antibody, is a first-line option in several settings; however, clinical benefit is variable and resistance frequently emerges. In preclinical models of bevacizumab-refractory disease, combining bevacizumab with inhibitors of lactate production improved therapeutic response [117]. Lactylation inhibition may also augment immunotherapy. Although immune checkpoint blockade is central to contemporary immunotherapy, response rates remain modest across most solid tumors. Notably, combining lactylation inhibitors with immune checkpoint inhibitors can restore sensitivity in otherwise non-responsive settings [19, 22]. suggesting a promising direction for improving outcomes in solid tumors. Tumor type may also influence the efficacy of lactylation-targeted therapy. Highly glycolytic tumors are characterized by increased lactate accumulation and enhanced lactylation, which may render them more responsive to such interventions. Conversely, tumors with low glycolytic activity may show limited sensitivity to lactylation-targeted strategies.

Despite rapid progress in the study of lactylation, several important limitations should be acknowledged. Firstly, most studies have focused on the detection of L-lactylation, whereas D-lactylation remains comparatively underexplored. In many cases, lactylation is assessed by immunoprecipitation followed by detection with pan-lactylation antibodies; however, these approaches alone cannot establish chemical specificity, site occupancy or functional causality. Site-resolved liquid chromatography–tandem mass spectrometry (LC–MS/MS) provides stronger evidence, but further validation is often required, as L-lactylation, D-lactylation and structurally related lysine modifications, such as N-ε-carboxyethyllysine, may be difficult to distinguish without isomer-specific approaches. Recent studies have therefore emphasized the importance of isomer-specific antibodies, chemical derivatization-based separation and targeted mass spectrometry for discriminating between L- and D-lactylation species. Ideally, candidate lactylation events should be supported by multiple layers of evidence, including antibody-based screening, high-confidence site-resolved mass spectrometry, isotope tracing where appropriate, site-directed mutagenesis, writer or eraser perturbation and functional rescue experiments. Secondly, the regulatory logic of lactylation is incompletely understood. Although multiple candidate writers and erasers have been proposed, their cell-type- and context-specific functions—and potential synergistic or antagonistic relationships—remain poorly defined. Second, studies of lactate utilization and oxidation have focused on a limited set of cell types and settings, leaving its broader roles in complex physiological environments unresolved. In particular, lactylation biology outside oncology remains underexplored, including in non-malignant systems such as the nervous and cardiovascular systems. Future work should delineate lactylation regulatory networks in greater depth. High-throughput proteomics will help identify additional enzymes and substrates, enabling the construction of more comprehensive network models. In parallel, functional studies across diverse cell types and physiological contexts are needed to define how lactylation shapes cellular differentiation, tissue development and organismal ageing. From a translational perspective, expanded preclinical evaluation and well-designed clinical trials should test lactylation- or lactate-axis inhibition in combination with immune checkpoint blockade to optimize regimens, improve efficacy and mitigate toxicity. Lactylation-linked metabolic states may also offer diagnostic value. For example, elevated LDH is associated with poorer outcomes to anti-PD-1 therapy in melanoma [22]. underscoring the potential utility of lactate-related biomarkers for patient stratification and therapeutic decision-making. As the field matures, the mechanisms sustaining high intratumoral lactate are likely to be clarified, informing improved treatment strategies for lactate-rich tumors.

Abbreviations

TME

Tumor microenvironment

MCTs

Monocarboxylate transporters

LDHB

Lactate dehydrogenase B

PTMs

Post-translational modifications

Kla

Lysine lactylation

CBP

CREB-binding protein

HDACs

Histone deacetylases

KMTs

Lysine methyltransferases

PRMTs

Protein arginine methyltransferases

LDHA

Lactate dehydrogenase A

GTPSCS

GTP-specific succinyl-CoA synthetase

GNAT

Gcn5-related N-acetyltransferase

DPF2

Double PHD fingers 2

H3K18la

H3K18 lactylation

SAH

Subarachnoid haemorrhage

BRD4

Bromodomain-containing protein 4

H4K8la

H4K8 lactylation

MGO

Methylglyoxal

LGSH

Lactoylglutathione

GSH

Glutathione

GLO2

Glyoxalase 2

GLO1

Glyoxalase 1

KCNK1

Potassium two-pore domain channel subfamily K member 1

IGF1R

Insulin-like growth factor 1 receptor

CRC

Colorectal cancer

HPV16

Human papillomavirus 16

G6PD

Glucose-6-phosphate dehydrogenase

PPP

Pentose phosphate pathway

PYCR1

Pyrroline-5-carboxylate reductase 1

H3K9la

H3K9 lactylation

RIG-I

Retinoic acid-inducible gene I

EMT

Epithelial–mesenchymal transition

MDH2

Malate dehydrogenase 2

MVBs

Multivesicular bodies

VEGFR2

Vascular endothelial growth factor receptor 2

VM

Vascular mimicry

VEGF

Vascular endothelial growth factor

MCT1

Monocarboxylate transporter 1

PDHK1

Pyruvate dehydrogenase kinase 1

EVA1A

Endogenous retrovirus group E member 1

CTLs

Cytotoxic T lymphocytes

TIMs

Tumor-infiltrating myeloid cells

ACSS2

Acetyl-CoA synthetase 2

KAT2A

Lysine acetyltransferase 2 A

Tregs

Regulatory T cells

TAM

Tumor-associated macrophage

MCM7

Minichromosome maintenance complex component 7

GOLPH3

Golgi phosphoprotein 3

NHEJ

Non-homologous end-joining

DSB

DNA double-strand break

MRN

MRE11–RAD50–NBS1

PI3K

Phosphatidylinositol 3-kinase

IGF2BP3

Insulin-like growth factor 2 mRNA-binding protein 3

NRF2

Nuclear factor erythroid 2-related factor 2

ENSA

Endosulfine-α

WTAP

Wilms tumor 1-associating protein

5-FU

5-fluorouracil

PRDX1

Peroxiredoxin 1

MVP

Major vault protein

β-TrCP

β-transducin repeat-containing protein

NK

Natural killer

NAD

Nicotinamide adenine dinucleotide

2-DG

2-Deoxy-D-glucose

HK2

Hexokinase 2

RJA

Royal jelly acid

DML

Demethylzeylasteral

LCSC

Liver cancer stem-cell

Authors' contributions

X.B., X.Y., J.W., M.P., M.S., Y.T. J.J. L.X. and M.X. collected the related paper and drafted the manuscript. Y.Y. and X.J. participated in the design of the review and draft the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported in part by grants from the following sources: the National Natural Science Foundation of China (82202966, 82573859), the Natural Science Foundation of Hunan Province (2024JJ6287, 2026JJ80901), the Natural Science Foundation of Sichuan Province (2026NSFSC0691), the science and technology innovation Program of Hunan Province (2023RC3199), Scientific Research Project of Hunan Provincial Health Commission (20256912), High-Level Talent Support Program of Hunan Cancer Hospital (20250805-1003, 20250807-1002), the Joint Funds for the Innovation of Science and Technology, Fujian Province (2025Y9120).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.