Qiang Yang1†
Hai Zhao- 1Department of Neurosurgery, The Second Affiliated Hospital of Lanzhou University, Lanzhou, Gansu, China
- 2Department of Neurosurgery, 3201 Hospital of Xi’an Jiaotong University Health Science Center, Hanzhong, Shaanxi, China
- 3Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
The discovery of lactylation, a post-translational modification derived from lactate, has fundamentally altered the perception of cancer metabolism. Once regarded as a metabolic waste product, lactate is now recognized as a central fuel source, a signaling molecule, and an epigenetic substrate capable of reprogramming gene expression and cellular function. Lactylation integrates metabolic reprogramming, tumor plasticity, and immune suppression, thereby orchestrating cancer initiation, progression, and resistance to therapy. This review provides a critical and integrative commentary on recent advances in lactylation biology, drawing from biochemical, epigenetic, and immunological perspectives. It synthesizes mechanistic insights into lactylation, highlights its role in tumorigenesis and the tumor microenvironment (TME), and evaluates therapeutic strategies that target lactate production, transport, and lactylation machinery. By dissecting consensus, controversies, and unresolved questions, we argue that lactylation represents both a hallmark of tumor adaptation and a potential Achilles’ heel for intervention. We further discuss future research directions, including comprehensive lactylome mapping, structural biology of lactylated proteins, microbiome-derived lactate, and clinical translation. Ultimately, lactylation is not merely a byproduct of glycolysis but a metabolic language that tumors employ to communicate, adapt, and thrive. Decoding this language may open new frontiers in cancer therapy.
Introduction
The Warburg effect, first described nearly a century ago, characterized the paradoxical preference of tumor cells for glycolysis even in the presence of oxygen (1, 2). For decades, this phenomenon reinforced the notion of lactate as a metabolic waste product, expelled from tumor cells into the extracellular environment to prevent acidosis and sustain glycolytic flux (3) (Figure 1). However, isotope tracing and metabolomic studies have since shattered this dogma. Lactate is now recognized as a major carbon source for oxidative phosphorylation and biosynthesis, frequently surpassing glucose in contribution to the tricarboxylic acid (TCA) cycle (4–6). This revelation repositions lactate as a central metabolite at the crossroads of energy production, redox regulation, and signaling.
Figure 1. Milestones in lactate and lactylation research. This timeline summarizes key discoveries from the identification of lactic acid in 1780 to recent advances in 2025. Highlights include the Warburg effect, the lactate shuttle, and emerging roles of histone and non-histone lactylation in metabolism, immunity, and disease progression.
The most transformative advance in this trajectory was the discovery of histone lysine lactylation (Kla) in 2019, which directly linked lactate metabolism to chromatin modification (7, 8). Lactylation demonstrated that lactate could function as an epigenetic substrate, modifying both histones and non-histone proteins to reprogram gene expression (9). Unlike acetylation or methylation, lactylation is acutely sensitive to metabolic flux, reflecting environmental conditions such as hypoxia, nutrient deprivation, and immune pressure (10). In cancer, where glycolysis is constitutively activated and lactate accumulates, lactylation emerges as a dynamic regulatory mechanism that confers adaptability, survival, and resistance (11).
Thus, lactylation represents more than a novel biochemical curiosity. It is a functional bridge between tumor metabolism and transcriptional control, providing mechanistic insight into how tumors integrate metabolic reprogramming with immune evasion and microenvironmental remodeling (12). The following sections critically examine these dimensions, moving from biochemical underpinnings to tumor initiation, TME remodeling, therapeutic strategies, controversies, and future perspectives.
Biochemical and epigenetic foundations of lactylation
The biochemical foundation of lactylation is closely tied to cellular lactate metabolism, and multiple donor pathways have now been identified. In mammalian cells, lactoyl-CoA has been quantitatively detected using LC–MS–based metabolomics, confirming its role as a principal acyl donor for lysine L-lactylation. Moreover, a recent study identified GTPSCS as a nuclear lactoyl-CoA synthetase catalyzing its formation, linking metabolic flux to histone and non-histone protein modification (13–16). Lactyl-CoA derives from lactate, itself produced primarily through lactate dehydrogenase A (LDHA)-mediated reduction of pyruvate. Continuous glycolysis ensures abundant substrate, while transport through monocarboxylate transporters (MCT1 and MCT4) regulates intracellular and extracellular lactate pools (17). In hypoxic tumor cores, lactate exported by MCT4 is taken up by oxygenated tumor regions through MCT1, fueling oxidative phosphorylation in a process termed the “lactate shuttle” (18, 19). This metabolic symbiosis enhances tumor resilience and expands metabolic heterogeneity.
The enzymatic regulation of lactylation is becoming increasingly well defined as new biochemical evidence emerges. Early studies suggested that the acetyltransferase p300 may participate in catalyzing lysine lactylation, and subsequent in vitro enzymology has provided direct support for p300-mediated L-lactyl transfer to histone substrates (8). Although the lactyltransferase activity of CBP is less well characterized, accumulating results indicate that p300—and potentially CBP—can function as bona fide “writers” of lysine lactylation in addition to their classical acetyltransferase roles (20). These findings raise fundamental questions about acyl-substrate competition. Rather than a simple replacement of acetylation by lactylation, current evidence suggests that fluctuations in intracellular metabolic flux—particularly glycolysis-driven lactate accumulation—may alter the relative availability of acyl donors, thereby influencing the balance between acetyl-CoA– and lactyl-CoA–dependent lysine acylation. However, whether lactyl-CoA reaches concentrations sufficient to broadly rewrite acylation patterns in vivo remains an open question. Equally important, lactylation is now recognized as a reversible modification. Class I histone deacetylases (HDAC1–3) and several sirtuins (SIRT1–3) have been experimentally confirmed to remove lactyl groups from histone and non-histone substrates both in vitro and in cells, demonstrating bona fide delactylase activity (21). These multifunctional deacylases indicate that lactylation does not persist longer than other post-translational modifications by default; rather, its stability is determined by enzyme activity, metabolic context, and chromatin environment. At present, whether additional, dedicated substrate-specific delactylases exist remains a subject of active investigation.
Although histone lactylation and acetylation target the same lysine residues (e.g., H3K18, H4K12) and share writer enzymes, they exhibit fundamentally distinct temporal kinetics and functional roles. Acetylation typically functions as a stable epigenetic mark, maintaining an open chromatin architecture essential for housekeeping genes and steady-state proliferation (22). The intracellular pool of acetyl-CoA is tightly regulated and relatively constant under physiological conditions, ensuring that acetylation provides a sustained structural foundation for cellular identity and lineage maintenance.
In sharp contrast, lactylation is characterized by rapid temporal dynamics, acting as a real-time sensor of metabolic flux rather than a static memory. Unlike the steady supply of acetyl-CoA, the concentration of lactyl-CoA fluctuates acutely in response to environmental stressors such as hypoxia or glucose deprivation (16). Studies indicate that histone lactylation levels can spike within hours of glycolytic activation, directly coupling the cell’s instantaneous metabolic status to its transcriptional output (23). This ‘metabolic plasticity’ allows lactylation to function as an ‘immediate-early’ epigenetic mechanism. While acetylation secures the transcription of cell-cycle genes, lactylation preferentially initiates transient, adaptive programs—such as stress tolerance, wound healing, and immune evasion—that are downregulated once metabolic homeostasis is restored. Thus, the shift from acetylation to lactylation represents a switch from ‘growth mode’ to ‘survival mode’ in the metabolically stressed tumor microenvironment.
Recent multi-omics profiling revealed that histone lactylation (notably H3K18la, H4K12la) upregulates ARG1, VEGFA, and M2 macrophage–associated genes, thereby promoting immunosuppressive polarization in the tumor microenvironment (24, 25). In tumor cells, elevated lactylation enhances expression of glycolytic enzymes (e.g., LDHA, PKM2) and stemness-related genes (e.g., SOX2, NANOG), contributing to metabolic reprogramming and cancer progression (26). Conversely, acetylation often regulates cell-cycle and proliferation-related transcriptional programs, whereas lactylation links directly to metabolic and inflammatory gene networks, suggesting distinct but partially overlapping transcriptional landscapes. This evidence supports the notion that excess lactyl-CoA may compete with acetyl-CoA, thereby redirecting lysine modifications toward lactylation-dependent transcriptional programs that reinforce tumor aggressiveness and immune evasion.
The functional consequences of lactylation extend across epigenetic and non-epigenetic domains (14). Histone lactylation alters chromatin accessibility, enhances transcription of glycolytic enzymes, and promotes oncogenic pathways such as EMT and lineage plasticity (23, 27, 28). Non-histone lactylation modifies proteins such as p53, impairing tumor-suppressor function, or nucleolar proteins such as NCL, which regulate RNA splicing and MAPK signaling (10, 25, 29). This duality underscores lactylation as both a transcriptional reprogrammed and a post-translational tuner of protein stability and function. Lactylation of nucleolin has been shown to exert pro-tumorigenic effects through dual regulation of RNA metabolism and mitogenic signaling. Functionally, lactylated NCL enhances alternative RNA splicing of proto-oncogenic transcripts, promoting the inclusion of exons that stabilize mRNAs encoding proteins such as MYC, BCL2, and MCL1. This splicing pattern supports tumor cell proliferation and survival. In parallel, lactylated NCL directly interacts with MAPK cascade components, including RAF1 and ERK1/2, thereby stabilizing the MAPK signaling complex and prolonging its cytoplasmic retention. The sustained activation of MAPK signaling subsequently amplifies the transcription of downstream effectors (e.g., ELK1, c-Fos), further enhancing tumorigenic potential (30).
Although histone lactylation is considered a widespread acyl modification, accumulating evidence indicates that its deposition across the genome is spatially and transcriptionally selective (31). Genome-wide ChIP-seq analyses have revealed that lactylation marks, particularly H3K18la and H4K12la, are enriched at promoters of glycolytic enzyme genes such as LDHA, PKM2, PFK1, and ENO1 (32). Beyond the well-characterized H3K18la, recent high-resolution mapping has unveiled biologically distinct roles for site-specific lactylation. H3K9la has been identified as a critical mark at promoters of pluripotency genes (e.g., OCT4, SOX2), driving cellular reprogramming and stemness maintenance in varying tumor contexts (28, 33). In the gene body, H4K79la is increasingly recognized for its role in facilitating transcriptional elongation, distinguishing it from promoter-centric modifications. Furthermore, H4K91la appears to regulate chromatin stability and nucleosome dynamics, acting as a structural checkpoint during DNA replication and repair (34). These findings suggest that the ‘lactyl code’ is far more complex than initially appreciated, with distinct sites governing specific phases of the transcription cycle and chromatin architecture.
This selectivity appears to arise from the physical coupling of metabolic enzymes with chromatin-modifying complexes. LDHA and p300/CBP co-localize at glycolytic gene loci, where locally produced lactate fuels site-specific lactyl-CoA synthesis, enabling preferential histone lactylation (35). Moreover, transcription factors such as HIF-1α and c-Myc, which are strongly activated under hypoxia and oncogenic signaling, directly recruit p300/CBP to glycolytic promoters, further facilitating lactylation-dependent transcriptional activation. Together, these findings support a metabolite–chromatin microdomain model, in which localized lactate accumulation and enzyme–chromatin co-assembly confer functional specificity to an otherwise broad histone modification, thereby selectively amplifying glycolytic transcription programs that sustain the Warburg phenotype.
The lactylation of p53 during tumor initiation is not merely a passive consequence of increased lactate accumulation but reflects a selectively regulated enzymatic process (36). Under hypoxic or glycolytic stress, the accumulation of nuclear lactate and its conversion to lactyl-CoA provide sufficient substrate for histone acetyltransferase-like enzymes, primarily p300/CBP and GCN5, which have been shown to catalyze p53 lactylation at specific lysine residues (e.g., K370, K382) (37).
Moreover, oncogenic signaling (e.g., HIF-1α and PI3K–AKT–mTOR) enhances both p300 nuclear recruitment and its lactyltransferase activity, conferring site-specific modification of p53 rather than a global acylation effect (38). Functionally, this modification suppresses p53’s DNA-binding affinity and transcriptional activation of target genes (CDKN1A/p21, BAX), thereby dampening cell-cycle arrest and apoptosis during early oncogenic transformation. Thus, p53 lactylation represents a metabolic-epigenetic convergence point, where elevated lactate levels and enzyme reprogramming cooperate to attenuate tumor-suppressive signaling and facilitate tumor initiation.
Beyond p300/CBP, several additional enzymes have been implicated in catalyzing or facilitating protein lactylation. For instance, KAT8 (also known as MOF) and TIP60 (KAT5), two members of the MYST family of acetyltransferases, were reported to catalyze histone lactylation under hypoxic or high-glycolytic conditions (39–41). Moreover, aminoacyl-tRNA synthetases such as AARS1 and AARS2 have been suggested to participate in the non-canonical transfer of lactyl groups to lysine residues in cytosolic and mitochondrial proteins (40, 42). Although their catalytic efficiencies remain under investigation, these findings expand the repertoire of potential “writers” beyond the classical acyltransferases, supporting their inclusion in Figure 2.
Figure 2. Interplay between lactate metabolism and protein lactylation. Lactate originates from both exogenous and endogenous sources. Exogenous lactate is transported into cells via monocarboxylate transporters (MCTs) and converted to lactyl-CoA, serving as a donor for histone and non-histone lactylation. Endogenous lactate arises from glycolysis, while under aerobic conditions pyruvate enters mitochondria to fuel the tricarboxylic acid (TCA) cycle.
Lactylation in tumor initiation and progression
The initiation of cancer is characterized by the inactivation of tumor suppressors and the activation of oncogenes, processes in which lactylation is now implicated. Lactylation of p53 impairs its transcriptional activation of DNA damage response genes, weakening cell-cycle checkpoints and apoptosis (43, 44). This modification offers a mechanistic explanation for how p53 dysfunction may occur independently of genetic mutations, broadening the spectrum of p53 inactivation mechanisms in cancer. Similarly, lactylation of NCL alters alternative splicing and activates MAPK signaling, promoting proliferation and resistance (29).
Histone lactylation drives tumor plasticity and adaptability. In neuroendocrine prostate cancer, H3K18la increases LDHA expression and remodels chromatin near neuronal lineage genes, facilitating lineage plasticity and resistance to androgen deprivation therapy (45, 46). In other cancers, lactylation regulates EMT transcription factors such as ZEB1(Zinc finger E-box-binding homeobox 1), endowing tumor cells with migratory and invasive potential (47). This highlights lactylation as a dynamic enabler of phenotypic transitions that underlie metastasis and relapse.
Although both acetylation and lactylation can occur at H3K18, these two modifications are mutually exclusive at the same residue but can coexist in different nucleosomes or at distinct genomic loci in a context-dependent manner (48). In neuroendocrine prostate cancer, metabolic reprogramming driven by oncogenic signaling pathways such as MYC, PI3K–AKT–mTOR, and HIF-1α enhances aerobic glycolysis and lactate accumulation, leading to elevated levels of intracellular lactyl-CoA (49, 50). Under these conditions, the histone acetyltransferases p300/CBP—which can use lactyl-CoA as an alternative acyl donor—serve as major “writers” of H3K18 lactylation. This process represents not a passive replacement of acetylation but an active enzymatic shift that favors lactylation in regions of high lactate flux, particularly at promoters and enhancers of genes related to metabolism, lineage plasticity, and stress adaptation (51). In this metabolic and epigenetic context, H3K18ac and H3K18la display dynamic redistribution rather than a simple gain–loss pattern. H3K18ac remains associated with proliferation and housekeeping gene loci, while H3K18la is preferentially deposited at metabolic and stemness-related genes, creating partially overlapping yet functionally distinct transcriptional landscapes. This competitive occupancy allows lactylation to confer transcriptional selectivity and explains the selective activation of glycolytic and neuroendocrine programs observed in neuroendocrine prostate cancer (52).
The increase in H3K18la thus arises from both the enhanced nuclear availability of lactyl-CoA and the context-specific recruitment of p300/CBP to responsive chromatin regions. Potential delactylases such as HDAC1–3 and SIRT family enzymes may counterbalance this modification, although their precise roles in neuroendocrine prostate cancer remain to be elucidated (53). Regarding ZEB1 regulation, studies in epithelial–mesenchymal transition and cancer stemness models indicate that H3K18la and H3K9la enrichment at ZEB1 regulatory elements correlates with transcriptional activation (46). While the exact histone residue responsible for this regulation in neuroendocrine prostate cancer has not been unequivocally mapped, current evidence supports a model in which lactylation at H3K18 or H3K9 promotes ZEB1 expression and facilitates lineage plasticity during tumor progression.
Equally important is the role of lactylation in therapy resistance. Lactylation-induced stabilization of HIF-1α promotes continued glycolysis and angiogenesis, sustaining tumors under therapeutic stress (32, 54). Lactylation also interfaces with drug efflux pumps and DNA repair proteins, further enhancing resistance (55, 56). Taken together, these findings underscore lactylation as a central driver of oncogenesis, plasticity, and resilience, with implications for early tumor initiation and late-stage progression (Figure 3).
Figure 3. Mechanistic pathways linking lactylation to tumorigenesis and chemoresistance.
The elevated levels of protein lactylation observed in cancer originate from the profound metabolic reprogramming that characterizes malignant cells (57, 58). The primary driver is the Warburg effect, in which persistent aerobic glycolysis leads to excessive lactate accumulation even under normoxic conditions (59). The elevated intracellular lactate pool serves as a substrate for lactyl-CoA synthesis, fueling histone and non-histone lactylation through p300/CBP and other acyltransferases (60). Beyond glycolytic flux, mitochondrial dysfunction and HIF-1α activation further amplify lactate production by enhancing LDHA expression and suppressing pyruvate oxidation. In parallel, monocarboxylate transporters (MCT1/4) dynamically redistribute lactate across tumor and stromal compartments, ensuring a constant supply of this metabolite for lactylation (61).
Recent advances have considerably expanded the catalog of lactylation-regulated proteins implicated in tumorigenesis, revealing that this post-translational modification influences a diverse array of cellular pathways that underlie malignant transformation. A pivotal example is HIF-1α, a central transcriptional regulator of metabolic adaptation. Under hypoxic conditions, tumor cells accumulate lactate due to enhanced glycolysis, and HIF-1α lactylation stabilizes the protein by reducing its ubiquitination and proteasomal degradation. This stabilization amplifies glycolytic gene transcription, vascular endothelial growth factor (VEGF) expression, and angiogenic signaling, forming a self-reinforcing metabolic loop that sustains tumor growth in hypoxic niches (32).
Another key node is pyruvate kinase M2 (PKM2), an enzyme critical for the Warburg effect. Lactylation of PKM2 on lysine residues modulates its structural conformation and subcellular localization. While unmodified PKM2 primarily drives glycolytic flux, its lactylated form translocates into the nucleus, where it serves as a coactivator for oncogenic transcription factors such as c-Myc and STAT3. This nuclear function enhances the transcription of glycolytic enzymes and cell-cycle regulators, reinforcing metabolic reprogramming and proliferation. Importantly, inhibition of PKM2 lactylation in preclinical models has been shown to reverse the Warburg phenotype and attenuate tumor aggressiveness, highlighting it as a potential therapeutic target (62).
Tumor suppressor p53, in contrast, represents an example of how lactylation undermines anti-tumor defenses. Lactylation of p53 at specific lysine residues—particularly within its DNA-binding domain—impairs its ability to transactivate downstream genes involved in cell-cycle arrest and apoptosis, such as p21 and BAX. Mechanistically, this modification reduces p53’s chromatin-binding affinity, resulting in diminished tumor-suppressive transcriptional activity and promoting oncogenic survival signaling. The interplay between acetylation and lactylation of p53 suggests that elevated lactate levels may tilt the post-translational balance toward a pro-tumorigenic state (44).
Similarly, YTHDF2 has recently been identified as a lactylation-sensitive oncogenic regulator. Lactylation enhances YTHDF2 expression and stability, thereby accelerating the degradation of tumor-suppressive mRNAs that contain m6A modifications. This modification-driven turnover of key inhibitory transcripts promotes tumor cell proliferation and immune evasion. The lactate–YTHDF2 axis thus represents a critical convergence point between metabolic signaling and RNA epigenetics, offering new opportunities for therapeutic intervention in glycolytic tumors (63, 64).
Beyond transcriptional and epigenetic regulation, lactylation also governs genomic stability and therapy response. MRE11 and NBS1, essential components of the MRN complex responsible for double-strand DNA break repair, undergo lactylation that enhances their nuclease activity and recruitment to damage sites. This modification facilitates efficient DNA repair and confers resistance to genotoxic stress, including radiation and platinum-based chemotherapies. Consequently, tumor cells with hyperlactylated MRE11/NBS1 display marked chemoresistance, and pharmacologic blockade of lactate production (via LDHA inhibition) restores therapeutic sensitivity (65, 66). In parallel, high-mobility group box 1 (HMGB1)—a chromatin-associated protein and extracellular alarmin—has been shown to undergo lactylation, which augments its translocation and secretion. Lactylated HMGB1 promotes the expression of proinflammatory cytokines and the recruitment of immunosuppressive myeloid cells, thereby linking lactate metabolism to the inflammatory TME. This reinforces a positive feedback loop between lactate accumulation, immune suppression, and tumor progression (67, 68).
Collectively, these emerging findings demonstrate that lactylation is not a passive byproduct of altered metabolism but rather a dynamic signaling mechanism that orchestrates metabolic adaptation, transcriptional reprogramming, genomic maintenance, and immune evasion. Through the coordinated modification of proteins such as HIF-1α, PKM2, p53, YTHDF2, MRE11/NBS1, and HMGB1, lactylation integrates oncogenic metabolism with tumor-promoting transcriptional and epigenetic circuits. Understanding these multifaceted roles provides not only a unifying framework for how metabolic reprogramming drives malignancy but also a rationale for targeting lactylation-dependent pathways in precision oncology. Emerging evidence suggests that oncogenic signaling pathways such as MYC, PI3K–AKT–mTOR, and KRAS mutations promote glycolytic enzyme expression and increase the cytosolic NADH/NAD+ ratio, further stabilizing lactate accumulation (69, 70). Epigenetic feedback loops exacerbate this state: lactylation of histones at glycolytic gene promoters (e.g., LDHA, PFK1) enhances their own transcription, creating a self-reinforcing circuit of hyperlactylation (35). Finally, tumor–stroma metabolic crosstalk also contributes. Cancer-associated fibroblasts and immune cells within the tumor microenvironment secrete lactate that can be imported by cancer cells or myeloid cells, sustaining the lactylation landscape across the entire tumor ecosystem (71). Collectively, these processes constitute a metabolic–epigenetic axis, whereby dysregulated glycolysis and lactate flux directly drive aberrant protein lactylation and malignant adaptation.
Lactylation and remodeling of the tumor microenvironment
The tumor microenvironment is increasingly recognized as a decisive determinant of cancer progression and therapy response (71–73). Lactylation plays a pivotal role in reprogramming immune and stromal components of the TME, thereby orchestrating an ecosystem that favors tumor survival (74). The elevated lactate in the TME originates primarily from aerobic glycolysis in rapidly proliferating tumor cells, a hallmark of the Warburg effect. Tumor cells convert glucose to lactate even under normoxic conditions, leading to a substantial accumulation of extracellular lactate. This lactate is exported through monocarboxylate transporters (MCT4 and MCT1) and acidifies the surrounding milieu, which profoundly shapes immune cell behavior (75). Once released, lactate is taken up by neighboring immune cells—such as macrophages, dendritic cells, and T cells—via MCT1, serving as both a metabolic substrate and a signaling molecule. Inside these immune cells, lactate can be converted into lactyl-CoA, which drives histone and non-histone lactylation to reprogram their functions toward immunosuppressive phenotypes (16).
In addition to tumor-derived lactate, certain immune subsets, including TAMs and myeloid-derived suppressor cells (MDSCs), can generate lactate intrinsically through glycolytic activation under hypoxia and inflammatory stimulation (76, 77). These immune-derived lactate pools may contribute to autocrine or paracrine lactylation, amplifying immunosuppressive feedback loops within the TME. Therefore, lactate accumulation in the TME represents a bidirectional metabolic exchange, dominated by tumor glycolysis but reinforced by immune cell metabolism, collectively sustaining a tolerogenic, pro-tumor environment.
Macrophages represent the most extensively studied immune population influenced by lactylation (78). High lactate concentrations drive histone lactylation in macrophages, skewing them toward an M2 immunosuppressive phenotype characterized by upregulation of anti-inflammatory cytokines and angiogenic factors (27). This epigenetic reprogramming sustains immune evasion and promotes vascularization. T cells and NK cells are likewise affected: lactate accumulation suppresses their cytotoxic activity, while lactylation of immune regulatory proteins may further consolidate their dysfunctional state (79, 80). Thus, lactylation acts as a metabolic immune checkpoint, functioning in parallel with PD-1/PD-L1 and CTLA-4 pathways (81, 82). While classical immune checkpoints such as PD-1/PD-L1 and CTLA-4 suppress antitumor immunity through receptor–ligand interactions that inhibit T-cell activation, lactylation functions as a “metabolic immune checkpoint” in a parallel but mechanistically distinct manner (83). Rather than blocking receptor signaling, lactylation remodels the metabolic and epigenetic landscape of both immune and tumor cells, establishing a suppressive tumor microenvironment. Specifically, lactate accumulation and subsequent histone and non-histone lactylation in macrophages promote polarization toward the M2-like immunosuppressive phenotype, characterized by high ARG1, IL-10, and VEGF expression (84). In T cells, elevated extracellular lactate impairs glycolysis and effector cytokine production, while histone lactylation in dendritic cells attenuates antigen presentation (85). Thus, lactylation and classical checkpoints converge functionally by restraining cytotoxic immunity yet act through distinct layers of regulation—one via metabolic–epigenetic reprogramming, the other via surface receptor signaling (14). The two axes may even cooperate: PD-L1 expression can be up-regulated under high-lactate conditions, suggesting that metabolic checkpoints such as lactylation can potentiate classical immune inhibitory pathways. This conceptual parallel underscores lactylation’s role as a fundamental regulator of immune tolerance in the tumor microenvironment.
Stromal fibroblasts and endothelial cells are also subject to lactylation-mediated reprogramming (86). In fibroblasts, lactylation enhances extracellular matrix remodeling, facilitating invasion and metastasis (86). In endothelial cells, lactylation promotes VEGFA expression and vascular permeability, supporting angiogenesis (32, 87). Together, these processes create a TME characterized by immune tolerance, stromal support, and enhanced vascular supply, all underpinned by lactylation as a unifying mechanism (Figure 4).
Figure 4. Lactate and lactylation as therapeutic vulnerabilities in cancer. Targeting lactate and lactylation represents a critical therapeutic vulnerability in cancer. Interventions directed against lactate/lactylation pathways can attenuate their role in oncogenic metabolic reprogramming and remodeling of the tumor microenvironment, highlighting their potential as an Achilles’ heel for effective cancer treatment.
Lactylation enhances oncogenic activity by upregulating YAP signaling while impairing the tumor-suppressive function of p53. In parallel, modification of MRE11 and NBS1 within the MRN complex strengthens homologous recombination–mediated DNA repair, thereby driving chemoresistance.
Systemic roles of lactylation across cancer biology
The biochemical foundation of lactylation lies in the cellular metabolism of lactate. As illustrated in Figure 2, both glycolytic and mitochondrial pathways converge on the formation of lactyl-CoA, which serves as the activated donor for lysine lactylation. Understanding this metabolic context is essential to appreciating how lactate availability regulates histone and non-histone protein modifications in cancer biology. While lactylation is often framed in the context of localized tumor metabolism, it is increasingly evident that its influence extends systemically, orchestrating metabolic adaptation across organs. Tumors act not as isolated metabolic islands but as nodes within a host-wide metabolic network. Lactate produced in tumors can circulate systemically, serving as a substrate for the liver, heart, and even the brain (88–90). This systemic lactate flux raises the possibility that lactylation might occur beyond the tumor boundaries, reshaping the biology of distant tissues.
Evidence from glioblastoma models indicates that lactylation contributes to the maintenance of glioma stem-like cells, endowing them with self-renewal and therapeutic resistance (91–94). In breast cancer, lactylation has been linked to estrogen receptor signaling, further connecting metabolic stress with hormone-driven proliferation (95–97). Lung cancers exhibit pronounced MCT1-mediated lactate utilization, with isotopic tracing studies demonstrating that lactate-derived TCA metabolites outcompete glucose-derived carbons (98, 99). In prostate cancer, lactylation supports the neuroendocrine phenotype and facilitates androgen independence, while in hepatocellular carcinoma it drives angiogenesis and immune suppression (100, 101). These tumor-specific manifestations underscore the context-dependent versatility of lactylation.
Beyond tumor-specific roles, lactylation intersects with lipid and amino acid metabolism. Lactate promotes glutaminolysis through c-Myc transcriptional regulation, enhancing the supply of α-ketoglutarate to the TCA cycle (23, 102). It also supports lipid biosynthesis by fueling acetyl-CoA pools and activating fatty acid synthase. Through these pathways, lactylation integrates diverse metabolic streams into oncogenic programs. Importantly, the convergence of lactylation with amino acid and lipid metabolism suggests that lactylation functions as a metabolic hub, directing nutrient utilization to optimize tumor fitness under stress (Figure 2).
Mechanistically, lactate regulates these anabolic processes through dual and complementary mechanisms. First, lactate acts as a signaling metabolite, stabilizing HIF-1α and activating c-Myc transcriptional programs that increase GLS1 and FASN expression, thereby sustaining glutaminolysis and lipogenesis (103). Lactate can also signal through G-protein-coupled receptor 81 (GPR81), which engages PI3K–AKT–mTOR signaling to further enhance lipid synthesis (104). Second, lactate serves as a substrate for histone and non-histone lactylation, providing an epigenetic layer of metabolic control. H3K18la and H4K12la enrichment at metabolic gene promoters opens chromatin and facilitates the recruitment of c-Myc, PPARγ(Peroxisome Proliferator-Activated Receptor Gamma), and SREBP1(Sterol Regulatory Element-Binding Protein 1), amplifying transcription of lipid- and amino-acid-metabolizing enzymes (105). Non-histone lactylation of enzymes such as PKM2 (Pyruvate Kinase M2 Isoform), ENO1 (Alpha-Enolase 1), and ACLY (ATP Citrate Lyase) has also been reported to boost glycolytic and lipogenic flux (106). Together, these findings indicate that lactate coordinates metabolic reprogramming through both signaling-dependent and lactylation-mediated mechanisms.
Therapeutic targeting of lactate and lactylation
Therapeutic efforts to exploit lactylation biology fall into three categories: inhibition of lactate production, blockade of lactate transport, and modulation of lactylation-specific enzymes. Each strategy presents distinct opportunities and limitations.
Targeting lactate production has long focused on LDHA, the primary enzyme catalyzing pyruvate reduction to lactate (107). LDHA inhibitors reduce lactate accumulation but face challenges of systemic toxicity and compensatory metabolic pathways (108). Nevertheless, LDHA remains an attractive target, particularly in tumors heavily dependent on glycolysis. Targeting LDHB, which catalyzes lactate oxidation, has also been proposed in cancers reliant on lactate as fuel (109).
Lactate transport represents a more advanced translational strategy. MCT1 and MCT4 are key transporters that maintain lactate homeostasis in tumors (110, 111). AZD3965, a selective MCT1 inhibitor, has reached phase I/II clinical trials for advanced solid tumors and non-Hodgkin lymphoma (112). Preliminary results show tolerability and pharmacodynamic evidence of target engagement, though efficacy outcomes remain under evaluation. The development of MCT4 inhibitors, such as VB124, aims to disrupt lactate efflux from hypoxic tumor cells, collapsing the metabolic symbiosis that sustains tumor heterogeneity (113) (Table 1).
Table 1. Representative clinical trials targeting lactate metabolism and related pathways in cancer.
The third approach involves direct modulation of lactylation enzymes. p300/CBP inhibitors such as SGC-CBP30 and PLX51107 reduce histone lactylation and attenuate tumor growth in preclinical models (114, 115). HDAC and sirtuin inhibitors, already deployed in cancer therapy, may function as “de-lactylases,” though their lack of specificity complicates interpretation (115, 116). The identification of bona fide lactylation-specific erasers would represent a transformative advance, enabling highly targeted interventions.
Perhaps the most compelling therapeutic avenue is combinatorial. Lactylation-induced immune suppression creates a rationale for pairing lactylation-targeted therapies with immune checkpoint inhibitors (ICIs) (79). Preclinical studies suggest that blocking lactate production or transport reactivates T cell function, sensitizing tumors to PD-1/PD-L1 blockade. Similarly, lactylation-targeted therapies may enhance CAR-T and NK cell therapies by alleviating metabolic constraints in the TME (79). Thus, lactylation targeting is unlikely to succeed as monotherapy but may play a decisive role in multi-pronged immunometabolism strategies.
Recent preclinical evidence suggests that the relationship between PD-1/PD-L1 signaling, and lactate metabolism is bidirectional (117, 118). While blocking lactate production or transport reactivates T-cell function and enhances responsiveness to immune checkpoint inhibitors, PD-1/PD-L1 blockade itself can also influence lactate metabolism (119). Several studies have demonstrated that anti–PD-1 or anti–PD-L1 therapy partially restores glycolytic activity in effector T cells, increasing glucose uptake and lactate release within the tumor microenvironment (118–120). However, this T-cell–derived lactate surge does not mirror the immunosuppressive lactate generated by tumor cells; instead, it reflects a metabolic rejuvenation that supports T-cell proliferation and cytokine production.
Conversely, tumor cells under PD-1/PD-L1 blockade often experience metabolic stress due to reactivated immunity and interferon signaling (121). This stress can transiently upregulate LDHA expression and activity, potentially increasing lactate output in resistant tumors as an adaptive survival mechanism (120). Such findings indicate that blocking PD-1/PD-L1 may dynamically reshape lactate metabolism on both immune and tumor sides, emphasizing the metabolic plasticity of the tumor microenvironment. Consequently, co-targeting lactylation and PD-1/PD-L1 pathways may overcome adaptive resistance by simultaneously disrupting tumor glycolysis and restoring immune effector function, providing a strong mechanistic rationale for combinatorial immunometabolic therapy.
Beyond cancer metabolism, lactate accumulation has broad systemic effects, as shown in Figure 5. Excess lactate contributes to pathological remodeling in multiple organ systems—such as the cardiovascular, respiratory, hepatic, and nervous systems—highlighting the translational relevance of lactate biology across diverse disease contexts. This systemic perspective strengthens the rationale for targeting lactylation therapeutically in cancer (Figure 5).
Figure 5. Pathophysiological roles of lactate across human diseases. Lactate has been implicated in the pathogenesis of a wide range of disorders, influencing the cardiovascular, respiratory, hepatic, urinary, and other organ systems. Beyond its metabolic functions, lactate serves as an important biomarker in the clinical diagnosis, monitoring, and prognosis of diverse diseases.
Consensus, controversies, and knowledge gaps
Several points of consensus have emerged across the literature. Lactylation is now firmly recognized as a critical link between metabolism and epigenetics (10, 122). Lactate functions not only as a fuel but also as a signaling molecule that drives epigenetic reprogramming and immune suppression (93, 123). Targeting lactate metabolism and lactylation holds promise for therapeutic intervention, with early-phase clinical trials underway.
Yet substantial controversies remain. One major debate concerns whether lactylation uniformly promotes tumor progression or whether it may exert context-specific suppressive roles. For example, some studies suggest that lactylation can stabilize pro-inflammatory gene expression in macrophages, potentially enhancing immune surveillance under certain conditions (27, 124, 125). This raises the possibility that lactylation may play dual roles, promoting or restraining cancer depending on cellular context and environmental cues.
Another unresolved issue is the existence of dedicated de-lactylases. Current evidence implicates HDACs and sirtuins in lactyl group removal, but whether these enzymes act specifically or incidentally remains unclear (126). The discovery of specialized lactylation erasers would reshape therapeutic strategies and provide tools for dissecting lactylation biology.
The temporal sequence of lactylation within the TME also remains contested. Does lactylation first occur in tumor cells, reshaping the microenvironment, or in infiltrating immune cells, which then establish immune tolerance? Clarifying this sequence is essential for determining optimal therapeutic timing and targets. Similarly, the role of stereoisomers—L-lactate versus D-lactate—remains poorly understood. While L-lactate predominates in mammalian metabolism, microbial-derived D-lactate may also contribute to host protein lactylation. Whether these isomers yield distinct functional outcomes is an open question with implications for microbiome–cancer interactions.
Finally, methodological challenges hinder progress. Detection of lactylation remains technically demanding, with antibody-based assays lacking specificity and mass spectrometry limited by sensitivity. Standardized detection platforms are needed to translate lactylation from discovery biology into clinical biomarkers.
Future directions
Future research must advance beyond descriptive studies toward mechanistic dissection and translational application. Comprehensive lactylome mapping across tumor types, disease stages, and treatment responses will be critical. Proteome-wide LC-MS/MS, integrated with chromatin immunoprecipitation and spatial transcriptomics, can reveal how lactylation distributes across histone and non-histone substrates, and how it shapes intratumoral heterogeneity. Such efforts will provide the blueprint for prioritizing lactylation events as therapeutic targets.
Equally urgent is the structural biology of lactylation. High-resolution cryo-EM and crystallography studies are needed to elucidate how lactylation alters protein conformation, stability, and protein–protein interactions. Without structural clarity, it remains difficult to predict which lactylation events drive oncogenesis and which are epiphenomena.
Moving beyond bulk tissue analysis, recent single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics studies have begun to map the “lactylome” at cellular resolution, revealing that lactylation is not uniformly distributed but defines specific, therapy-resistant cell states (127).
First, cell-state specificity has been identified as a key driver of resistance. For instance, in bladder cancer, scRNA-seq analysis isolated a distinct subpopulation of cisplatin-resistant epithelial cells characterized by hyper-lactylation (specifically H3K18la) (128). This state was driven by the transcription factors YBX1 and YY1, which locked cells into a glycolytic and drug-resistant phenotype impossible to detect in bulk samples. Similarly, in acute myeloid leukemia (AML), single-cell profiling revealed that high “lactylation scores” were restricted to malignant progenitor populations, which correlated with the recruitment of Tregs and M2 macrophages, thereby creating a localized immunosuppressive niche (129).
Second, spatial transcriptomics has added a geographic dimension to these findings. In glioblastoma, multi-omics integration demonstrated that lactylation-high clusters (marked by S100A6 expression) are not randomly dispersed but are spatially confined to hypoxic tumor cores and perinecrotic regions (130). These “lactylation niches” spatially overlap with immunosuppressive macrophages, suggesting that metabolic crosstalk is strictly compartmentalized. In ovarian cancer, resistant subpopulations exhibiting high ALDH1A1 and S100A4 expression were found to co-localize with lactylation signals, linking metabolic reprogramming directly to spatial stemness niches (131, 132).
Therefore, future research must utilize these high-resolution technologies not just to catalogue modifications, but to dissect the spatial topography of lactylation. Identifying the specific “lactylation-high” subclones that survive therapy and seed metastasis will be critical for developing precision inhibitors that target the most dangerous tumor populations while sparing healthy tissue.
The microbiome represents a largely unexplored frontier. Commensal bacteria, particularly Lactobacillus species, produce D-lactate through fermentation. Whether microbial-derived lactate contributes to host protein lactylation remains unknown, but the possibility of microbiome–epigenome crosstalk is tantalizing. If validated, this could open new therapeutic avenues involving dietary modulation, probiotics, or microbiota-targeted drugs.
Clinical translation demands that lactylation be incorporated into biomarker development. Profiling lactylation in tumor biopsies and circulating tumor cells may yield predictive markers of immunotherapy response. Furthermore, embedding lactylation profiling in clinical trials of ICIs, CAR-T, or metabolic inhibitors will clarify whether lactylation can serve as a stratification tool. Ultimately, lactylation-based diagnostics could guide patient selection, identify resistance mechanisms, and inform combination regimens.
Conclusion
Lactylation has emerged as a paradigm-shifting concept in cancer biology, embodying the convergence of metabolism, epigenetics, and immune regulation. By directly linking lactate accumulation to chromatin remodeling and protein regulation, lactylation explains how tumors exploit metabolic stress to drive adaptability, immune evasion, and therapy resistance.
Yet lactylation remains an unfinished story. Key questions regarding its enzymatic regulation, functional specificity, and therapeutic exploitability demand urgent answers. Its dualistic potential—sometimes oncogenic, sometimes immunostimulatory—remains underexplored. Methodological limitations continue to impede translation, and clinical validation has only begun.
Nevertheless, the trajectory of discovery is clear. Lactylation is not merely a biochemical curiosity but a metabolic language by which tumors orchestrate survival. Decoding and silencing this language may enable the next generation of therapies that integrate metabolic inhibition, epigenetic modulation, and immunotherapy. By recognizing lactylation as both a hallmark of tumor adaptation and a potential Achilles’ heel, the field now stands poised to convert a once-dismissed metabolite into a cornerstone of precision oncology.
Author contributions
QY: Software, Writing – original draft. ZY: Resources, Writing – original draft, Methodology. HZ: Funding acquisition, Supervision, Writing – review & editing, Methodology.
Funding
The author(s) declared financial support was received for this work and/or its publication. This work was supported by the Shandong Province Natural Science Foundation grants (grant no. ZR2022QH372).
Conflict of interest
The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Warburg O, Wind F, and Negelein E. The metabolism of tumors in the body. J Gen Physiol. (1927) 8:519–30. doi: 10.1085/jgp.8.6.519
2. Crabtree HG. Observations on the carbohydrate metabolism of tumours. Biochem J. (1929) 23:536. doi: 10.1042/bj0230536
3. Rabinowitz JD and Enerbäck S. Lactate: the ugly duckling of energy metabolism. Nat Metab. (2020) 2:566–71. doi: 10.1038/s42255-020-0243-4
4. Mao Y, Zhang J, Zhou Q, He X, Zheng Z, Wei Y, et al. Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation. Cell Res. (2024) 34:13–30. doi: 10.1038/s41422-023-00864-6
5. Keane C and Finlay DK. Natural killer loops: pyruvate in, lactate out. Nat Metab. (2025) 7:239–41. doi: 10.1038/s42255-024-01195-5
6. Cai H, Chen X, Liu Y, Chen Y, Zhong G, Chen X, et al. Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation. Nat Commun. (2025) 16:3230. doi: 10.1038/s41467-025-58563-2
7. Izzo LT and Wellen KE. Histone lactylation links metabolism and gene regulation. Nature (2019) 574:492–3. doi: 10.1038/d41586-019-03122-1
8. Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature. (2019) 574:575–80. doi: 10.1038/s41586-019-1678-1
9. Kotsiliti E. Lactylation and HCC progression. Nat Rev Gastroenterol Hepatol. (2023) 20:131. doi: 10.1038/s41575-023-00746-7
10. Ren H, Tang Y, and Zhang D. The emerging role of protein L-lactylation in metabolic regulation and cell signalling. Nat Metab. (2025) 7:647–64. doi: 10.1038/s42255-025-01259-0
11. Chen J, Huang Z, Chen Y, Tian H, Chai P, Shen Y, et al. Lactate and lactylation in cancer. Signal Transduct Target Ther. (2025) 10:38. doi: 10.1038/s41392-024-02082-x
12. Li H, Sun L, Gao P, and Hu H. Lactylation in cancer: Current understanding and challenges. Cancer Cell. (2024) 42:1803–7. doi: 10.1016/j.ccell.2024.09.006
13. Sheng X, Lin H, Cole PA, and Zhao Y. Biochemistry and regulation of histone lysine l-lactylation. Nat Rev Mol Cell Biol. (2025) 19:1–15. doi: 10.1038/s41580-025-00876-7
14. Hou X, Hong Z, Zen H, Zhang C, Zhang P, Ma D, et al. Lactylation in cancer biology: Unlocking new avenues for research and therapy. Cancer Commun (Lond). (2025) 45:1367–406. doi: 10.1002/cac2.70054
15. Hu Y, He Z, Li Z, Wang Y, Wu N, Sun H, et al. Lactylation: the novel histone modification influence on gene expression, protein function, and disease. Clin Epigenetics. (2024) 16:72. doi: 10.1186/s13148-024-01682-2
16. Liu R, Ren X, Park YE, Feng H, Sheng X, Song X, et al. Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis. Cell Metab. (2025) 37:377–94. doi: 10.1016/j.cmet.2024.11.005
17. Nian F, Qian Y, Xu F, Yang M, Wang H, and Zhang Z. LDHA promotes osteoblast differentiation through histone lactylation. Biochem Biophys Res Commun. (2022) 615:31–5. doi: 10.1016/j.bbrc.2022.05.028
18. Pérez de Heredia F, Wood IS, and Trayhurn P. Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, and MCT4) expression in human adipocytes. Pflügers Arch J Physiol. (2010) 459:509–18. doi: 10.1007/s00424-009-0750-3
19. Brooks GA. The science and translation of lactate shuttle theory. Cell Metab. (2018) 27:757–85. doi: 10.1016/j.cmet.2018.03.008
20. Moreno-Yruela C, Zhang D, Wei W, Bæk M, Liu W, Gao J, et al. Class I histone deacetylases (HDAC1–3) are histone lysine delactylases. Sci Adv. (2022) 8:eabi6696. doi: 10.1126/sciadv.abi6696
21. Encarnacion-Guevara S and Gil J. Expanding the landscape of lysine acetylation stoichiometry and clinical impact. J Proteomics. (2025) 30:105522. doi: 10.1016/j.jprot.2025.105522
22. Miziak P, Baran M, Borkiewicz L, Trombik T, and Stepulak A. Acetylation of histone H3 in cancer progression and prognosis. Int J Mol Sci. (2024) 25:10982. doi: 10.3390/ijms252010982
23. Li Y, Cao Q, Hu Y, He B, Cao T, Tang Y, et al. Advances in the interaction of glycolytic reprogramming with lactylation. BioMed Pharmacother. (2024) 177:116982. doi: 10.1016/j.biopha.2024.116982
24. Hou J, Guo M, Li Y, and Liao Y. Lactylated histone H3K18 as a potential biomarker for the diagnosis and prediction of the severity of pancreatic cancer. Clinics. (2025) 80:100544. doi: 10.1016/j.clinsp.2024.100544
25. Peng X and Du J. Histone and non-histone lactylation: molecular mechanisms, biological functions, diseases, and therapeutic targets. Mol Biomed. (2025) 6:38. doi: 10.1186/s43556-025-00275-6
26. Dong Q, Yang X, Wang L, Zhang Q, Zhao N, Nai S, et al. Lactylation of Hdac1 regulated by Ldh prevents the pluripotent-to-2C state conversion. Stem Cell Res Ther. (2024) 15:415. doi: 10.1186/s13287-024-04027-1
27. Bao C, Ma Q, Ying X, Wang F, Hou Y, Wang D, et al. Histone lactylation in macrophage biology and disease: from plasticity regulation to therapeutic implications. EBioMedicine. (2025) 111:105502. doi: 10.1016/j.ebiom.2024.105502
28. Niu Z, Chen C, Wang S, Lu C, Wu Z, Wang A, et al. HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription. Nat Commun. (2024) 15:3561. doi: 10.1038/s41467-024-47900-6
29. Yang L, Niu K, Wang J, Shen W, Jiang R, Liu L, et al. Nucleolin lactylation contributes to intrahepatic cholangiocarcinoma pathogenesis via RNA splicing regulation of MADD. J Hepatol. (2024) 81:651–66. doi: 10.1016/j.jhep.2024.04.010
30. Xu X, Wu X, Jin D, Ji J, Wu T, Huang M, et al. Lactylation: the regulatory code of cellular life activity and a barometer of diseases. Cell Oncol. (2025) 48:1203–17. doi: 10.1007/s13402-025-01083-4
31. Zhao B, Lan Z, Li C, and Wang H. Roles of lactylation in lipid metabolism and related diseases. Cell Death Discov. (2025) 11:401. doi: 10.1038/s41420-025-02705-4
32. Li C, Fu C, Zhou W, Li H, Liu Z, Wu G, et al. Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition. Cell Commun Signal. (2025) 23:364. doi: 10.1186/s12964-025-02366-x
33. Zhang C, Yu R, Li S, Yuan M, Hu T, Liu J, et al. KRAS mutation increases histone H3 lysine 9 lactylation (H3K9la) to promote colorectal cancer progression by facilitating cholesterol transporter GRAMD1A expression. Cell Death Differ. (2025) 32:2225–38. doi: 10.1038/s41418-025-01533-4
34. Liu J, Zhao L, Yan M, Jin S, Shang L, Wang J, et al. H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer. J Exp Clin Cancer Res. (2025) 44:252. doi: 10.1186/s13046-025-03512-6
35. Wang C and Ma X. The role of acetylation and deacetylation in cancer metabolism. Clin Transl Med. (2025) 15:e70145. doi: 10.1002/ctm2.70145
36. Ma J, Dai Y, Da W, Zhang Y, Bao P, Zhu W, et al. Lactylation affects p53 Nuclear Translocation to Promote Colorectal Cancer Progression. (2025). doi: 10.21203/rs.3.rs-5586218/v1
37. Fei X, Chen L, Gao J, Jiang X, Sun W, Cheng X, et al. p53 lysine-lactylated modification contributes to lipopolysaccharide-induced proinflammatory activation in BV2 cell under hypoxic conditions. Neurochem Int. (2024) 178:105794. doi: 10.1016/j.neuint.2024.105794
38. Zhang Y, Brown K, Yu Y, Ibrahim Z, Zandian M, Xuan H, et al. Nuclear condensates of p300 formed though the structured catalytic core can act as a storage pool of p300 with reduced HAT activity. Nat Commun. (2021) 12:4618. doi: 10.1038/s41467-021-24950-8
39. Xie B, Zhang M, Li J, Cui J, Zhang P, Liu F, et al. KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis. Proc Natl Acad Sci. (2024) 121:e2314128121. doi: 10.1073/pnas.2314128121
40. Zong Z, Ren J, Yang B, Zhang L, and Zhou F. Emerging roles of lysine lactyltransferases and lactylation. Nat Cell Biol. (2025) 27:563–74. doi: 10.1038/s41556-025-01635-8
41. Zhang S, Xie B, Zhu X, Dong S, and Li M. Lactylation in cancer: Unveiling new layers of complexity. Innov. (2025) 6:100914. doi: 10.1016/j.xinn.2025.100914
42. Gao L, Guo J, and Jia R. AARS1 and AARS2: from protein synthesis to lactylation-driven oncogenesis. Biomolecules. (2025) 15:1323. doi: 10.3390/biom15091323
43. Jiang X, Yang Y, Li X, Li T, Yu T, and Fu X. Lactylation: an innovative approach to disease control. Aging Dis. (2024) 16:2130. doi: 10.14336/AD.2024.0918
44. Wu Z, Peng Y, Chen W, Xia F, Song T, and Ke Q. Lactylation-driven transcriptional activation of FBXO33 promotes gallbladder cancer metastasis by regulating p53 polyubiquitination. Cell Death Dis. (2025) 16:144. doi: 10.1038/s41419-025-07372-y
45. Li W, Zhou C, Yu L, Hou Z, Liu H, Kong L, et al. Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer. Autophagy. (2024) 20:114–30. doi: 10.1080/15548627.2023.2249762
46. Raychaudhuri D, Singh P, Chakraborty B, Hennessey M, Tannir AJ, Byregowda S, et al. Histone lactylation drives CD8+ T cell metabolism and function. Nat Immunol. (2024) 25:2140–51. doi: 10.1038/s41590-024-01985-9
47. Wang R, Xu F, Yang Z, Cao J, Hu L, and She Y. The mechanism of PFK-1 in the occurrence and development of bladder cancer by regulating ZEB1 lactylation. BMC Urol. (2024) 24:59. doi: 10.1186/s12894-024-01444-5
48. Zhao Y, Zhang M, Huang X, Liu J, Sun Y, Zhang F, et al. Lactate modulates zygotic genome activation through H3K18 lactylation rather than H3K27 acetylation. Cell Mol Life Sci. (2024) 81:298. doi: 10.1007/s00018-024-05349-2
49. Xu P, Yang JC, Chen B, Ning S, Zhang X, Wang L, et al. Proteostasis perturbation of N-Myc leveraging HSP70 mediated protein turnover improves treatment of neuroendocrine prostate cancer. Nat Commun. (2024) 15:6626. doi: 10.1038/s41467-024-50459-x
50. Pungsrinont T, Kallenbach J, and Baniahmad A. Role of PI3K-AKT-mTOR pathway as a pro-survival signaling and resistance-mediating mechanism to therapy of prostate cancer. Int J Mol Sci. (2021) 22:11088. doi: 10.3390/ijms222011088
51. Wan L, Zhang H, Liu J, He Q, Zhao J, Pan C, et al. Lactylation and human disease. Expert Rev Mol Med. (2025) 27:e10. doi: 10.1017/erm.2025.3
52. Wang Y, Wang Y, Ci X, Choi SYC, Crea F, Lin D, et al. Molecular events in neuroendocrine prostate cancer development. Nat Rev Urol. (2021) 18:581–96. doi: 10.1038/s41585-021-00490-0
53. Li J, Lu L, Liu L, Ren X, Chen J, Yin X, et al. HDAC1/2/3 are major histone desuccinylases critical for promoter desuccinylation. Cell Discov. (2023) 9:85. doi: 10.1038/s41421-023-00573-9
54. Wu H, Huang H, and Zhao Y. Interplay between metabolic reprogramming and post-translational modifications: from glycolysis to lactylation. Front Immunol. (2023) 14:1211221. doi: 10.3389/fimmu.2023.1211221
55. Zeng Y, Jiang H, Chen Z, Xu J, Zhang X, Cai W, et al. Histone lactylation promotes multidrug resistance in hepatocellular carcinoma by forming a positive feedback loop with PTEN. Cell Death Dis. (2025) 16:59. doi: 10.1038/s41419-025-07359-9
56. Chen H, Li Y, Li H, Chen X, Fu H, Mao D, et al. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature. (2024) 631:663–9. doi: 10.1038/s41586-024-07620-9
57. Xu K, Shou Y, Liu R, Xiong H, Dai X, Bao X, et al. Lactylation in cancer: Advances and opportunities for treatment resistance. Clin Transl Med. (2025) 15:e70478. doi: 10.1002/ctm2.70478
58. Wang W, Wang H, Wang Q, Yu X, and Ouyang L. Lactate-induced protein lactylation in cancer: functions, biomarkers and immunotherapy strategies. Front Immunol. (2025) 15:1513047. doi: 10.3389/fimmu.2024.1513047
59. Zhang W, Xia M, Li J, Liu G, Sun Y, Chen X, et al. Warburg effect and lactylation in cancer: mechanisms for chemoresistance. Mol Med. (2025) 31:146. doi: 10.1186/s10020-025-01205-6
60. Zhang D, Liang C, Wu C, Hawanga M, Wan S, Xu L, et al. Nonhistone lactylation: A hub for tumour metabolic reprogramming and epigenetic regulation. J Transl Med. (2025) 23:901. doi: 10.1186/s12967-025-06813-8
61. Faghihkhorasani F, Moosavi M, Rasool Riyadh Abdulwahid A, Kavei M, Karimi S, Seyed Karimi M, et al. Role of monocarboxylate transporters in cancer immunology and their therapeutic potential. Br J Pharmacol. (2025) 182:4421–57. doi: 10.1111/bph.70110
62. Jin H, Wu P, Lv C, Zhang S, Zhang Y, Li C, et al. Mannose inhibits PKM2 lactylation to induce pyroptosis in bladder cancer and activate antitumor immune responses. Commun Biol. (2025) 8:689. doi: 10.1038/s42003-025-08130-8
63. Wang J and Lu A. The biological function of m6A reader YTHDF2 and its role in human disease. Cancer Cell Int. (2021) 21:109. doi: 10.1186/s12935-021-01807-0
64. Xiao S, Duan S, Caligiuri MA, Ma S, and Yu J. YTHDF2: a key RNA reader and antitumor target. Trends Immunol. (2025) 46:485–98. doi: 10.1016/j.it.2025.04.003
65. Kim S, Yamada S, Li T, Canasto-Chibuque C, Kim JH, Marcet-Ortega M, et al. Mouse MRE11-RAD50-NBS1 is needed to start and extend meiotic DNA end resection. Nat Commun. (2025) 16:3613. doi: 10.1038/s41467-025-57928-x
66. Chen Y, Wu J, Zhai L, Zhang T, Yin H, Gao H, et al. Metabolic regulation of homologous recombination repair by MRE11 lactylation. Cell. (2024) 187:294–311. doi: 10.1016/j.cell.2023.11.022
67. Zhu L, Zheng Q, Liu X, Ding H, Ma M, Bao J, et al. HMGB1 lactylation drives neutrophil extracellular trap formation in lactate-induced acute kidney injury. Front Immunol. (2025) 15:1475543. doi: 10.3389/fimmu.2024.1475543
68. Yang K, Fan M, Wang X, Xu J, Wang Y, Tu F, et al. Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis. Cell Death Differ. (2022) 29:133–46. doi: 10.1038/s41418-021-00841-9
69. Liu H, Zhao Z, Wu C, Chen J, He Z, and Jiang K. ZMYND8 promotes the Warburg effect and tumorigenesis through c-Myc activation in pancreatic cancer. Oncogene. (2025) 44:3083–95. doi: 10.1038/s41388-025-03483-0
70. Jiang M, Zhang K, Zhang Z, Zeng X, Huang Z, Qin P, et al. Pi3k/akt/mtor axis in cancer: from pathogenesis to treatment. MedComm. (2025) 6:e70295. doi: 10.1002/mco2.70295
71. Lan X, Li W, Zhao K, Wang J, Li S, and Zhao H. Revisiting the role of cancer-associated fibroblasts in tumor microenvironment. Front Immunol. (2025) 16:1582532. doi: 10.3389/fimmu.2025.1582532
72. Zhao Y and Zhao H. Dissecting the intratumoral microbiome landscape in lung cancer. Front Immunol. (2025) 16:1614731. doi: 10.3389/fimmu.2025.1614731
73. Che S, Yan Z, Feng Y, and Zhao H. Unveiling the intratumoral microbiota within cancer landscapes. Iscience. (2024) 27:109893. doi: 10.1016/j.isci.2024.109893
74. Dai E, Wang W, Li Y, Ye D, and Li Y. Lactate and lactylation: Behind the development of tumors. Cancer Lett. (2024) 591:216896. doi: 10.1016/j.canlet.2024.216896
75. Bonen A, Tonouchi M, Miskovic D, Heddle C, Heikkila JJ, and Halestrap AP. Isoform-specific regulation of the lactate transporters MCT1 and MCT4 by contractile activity. Am J Physiol Metab. (2000) 279:E1131–8. doi: 10.1152/ajpendo.2000.279.5.E1131
76. Jin X, Zhang N, Yan T, Wei J, Hao L, Sun C, et al. Lactate-mediated metabolic reprogramming of tumor-associated macrophages: implications for tumor progression and therapeutic potential. Front Immunol. (2025) 16:1573039. doi: 10.3389/fimmu.2025.1573039
77. Goldmann O and Medina E. Metabolic pathways fueling the suppressive activity of myeloid-derived suppressor cells. Front Immunol. (2024) 15:1461455. doi: 10.3389/fimmu.2024.1461455
78. Xu B, Liu Y, Li N, and Geng Q. Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues. Front Immunol. (2024) 15:1395786. doi: 10.3389/fimmu.2024.1395786
79. Hao Z-N, Tan X-P, Zhang Q, Li J, Xia R, and Ma Z. Lactate and lactylation: dual regulators of T-cell-mediated tumor immunity and immunotherapy. Biomolecules. (2024) 14:1646. doi: 10.3390/biom14121646
80. Jin J, Yan P, Wang D, Bai L, Liang H, Zhu X, et al. Targeting lactylation reinforces NK cell cytotoxicity within the tumor microenvironment. Nat Immunol. (2025) 26:1099–112. doi: 10.1038/s41590-025-02178-8
81. Huang Z-W, Zhang X-N, Zhang L, Liu L-L, Zhang J-W, Sun Y-X, et al. STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia. Signal Transduct Target Ther. (2023) 8:391. doi: 10.1038/s41392-023-01605-2
82. Zha J, Zhang J, Lu J, Zhang G, Hua M, Guo W, et al. A review of lactate-lactylation in Malignancy: its potential in immunotherapy. Front Immunol. (2024) 15:1384948. doi: 10.3389/fimmu.2024.1384948
83. Wang H, Yang J, Li X, and Zhao H. Current state of immune checkpoints therapy for glioblastoma. Heliyon. (2024) 10:e24729. doi: 10.1016/j.heliyon.2024.e24729
84. Noe JT, Rendon BE, Geller AE, Conroy LR, Morrissey SM, Young LEA, et al. Lactate supports a metabolic-epigenetic link in macrophage polarization. Sci Adv. (2021) 7:eabi8602. doi: 10.1126/sciadv.abi8602
85. Sangsuwan R, Thuamsang B, Pacifici N, Allen R, Han H, Miakicheva S, et al. Lactate exposure promotes immunosuppressive phenotypes in innate immune cells. Cell Mol Bioeng. (2020) 13:541–57. doi: 10.1007/s12195-020-00652-x
86. Liang L, Yang X, Yao S, Li X, and Wang F. Identification of lactylation-associated fibroblast subclusters predicting prognosis and cancer immunotherapy response in colon cancer. Gene. (2025) 940:149220. doi: 10.1016/j.gene.2025.149220
87. Fan W, Zeng S, Wang X, Wang G, Liao D, Li R, et al. A feedback loop driven by H3K9 lactylation and HDAC2 in endothelial cells regulates VEGF-induced angiogenesis. Genome Biol. (2024) 25:165. doi: 10.1186/s13059-024-03308-5
88. Cheng S, Xiao X, Wang D, Wang X, and Yang M. Lactate and lactylation in liver diseases: energy metabolism, inflammatory immunity and tumor microenvironment. Front Immunol. (2025) 16:1581582. doi: 10.3389/fimmu.2025.1581582
89. Ghosh-Choudhary S and Finkel T. Lactylation regulates cardiac function. Cell Res. (2023) 33:653–4. doi: 10.1038/s41422-023-00857-5
90. Han M, He W, Zhu W, and Guo L. The role of protein lactylation in brain health and disease: current advances and future directions. Cell Death Discov. (2025) 11:213. doi: 10.1038/s41420-025-02408-w
91. Wang H, Yang J, Li X, and Zhao H. Heliyon Current state of immune checkpoints therapy for glioblastoma. Heliyon. (2024) 10:e24729. doi: 10.1016/j.heliyon.2024.e24729
92. Zhou Z, Yin X, Sun H, Lu J, Li Y, Fan Y, et al. PTBP1 lactylation promotes glioma stem cell maintenance through PFKFB4-driven glycolysis. Cancer Res. (2025) 85:739–57. doi: 10.1158/0008-5472.CAN-24-1412
93. Qiu Q, Deng H, Song P, Liu Y, and Zhang M. Lactylation in glioblastoma: A novel epigenetic modifier bridging epigenetic plasticity and metabolic reprogramming. Int J Mol Sci. (2025) 26:3368. doi: 10.3390/ijms26073368
94. Wang H, Liu Y, Che S, Li X, Tang D, Lv S, et al. Deciphering the link: ferroptosis and its role in glioma. Front Immunol. (2024) 15:1–2. doi: 10.3389/fimmu.2024.1346585
95. Deng J and Liao X. Lysine lactylation (Kla) might be a novel therapeutic target for breast cancer. BMC Med Genomics. (2023) 16:283. doi: 10.1186/s12920-023-01726-1
96. Qiao Y, Liu Y, Ran R, Zhou Y, Gong J, Liu L, et al. Lactate metabolism and lactylation in breast cancer: mechanisms and implications. Cancer Metastasis Rev. (2025) 44:1–24. doi: 10.1007/s10555-025-10264-4
97. Huang L, Chen X, Yan M, Xiang Z, and Wu J. Lactate and lactylation in breast cancer: current understanding and therapeutic opportunities. Cancer Biol Med. (2025) 22:789–805. doi: 10.20892/j.issn.2095-3941.2025.0173
98. Ma R, Li X, Gong S, Ge X, Zhu T, Ge X, et al. Dual roles of lactate in EGFR-TKI-resistant lung cancer by targeting GPR81 and MCT1. J Oncol. (2022) 2022:3425841. doi: 10.1155/2022/3425841
99. Zhang C, Zhou L, Zhang M, Du Y, Li C, Ren H, et al. H3k18 lactylation potentiates immune escape of non–small cell lung cancer. Cancer Res. (2024) 84:3589–601. doi: 10.1158/0008-5472.CAN-23-3513
100. Luo Y, Yang Z, Yu Y, and Zhang P. HIF1α lactylation enhances KIAA1199 transcription to promote angiogenesis and vasculogenic mimicry in prostate cancer. Int J Biol Macromol. (2022) 222:2225–43. doi: 10.1016/j.ijbiomac.2022.10.014
101. Yang Z, Yan C, Ma J, Peng P, Ren X, Cai S, et al. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma. Nat Metab. (2023) 5:61–79. doi: 10.1038/s42255-022-00710-w
102. Zhang D, Gao J, Zhu Z, Mao Q, Xu Z, Singh PK, et al. Lysine L-lactylation is the dominant lactylation isomer induced by glycolysis. Nat Chem Biol. (2025) 21:91–9. doi: 10.1038/s41589-024-01680-8
103. Liao Y, Chen Q, Liu L, Huang H, Sun J, Bai X, et al. Amino acid is a major carbon source for hepatic lipogenesis. Cell Metab. (2024) 36:2437–48. doi: 10.1016/j.cmet.2024.10.001
104. Liu X, Li S, Cui Q, Guo B, Ding W, Liu J, et al. Activation of GPR81 by lactate drives tumour-induced cachexia. Nat Metab. (2024) 6:708–23. doi: 10.1038/s42255-024-01011-0
105. Plebanek MP, Xue Y, Nguyen Y-V, DeVito NC, Wang X, Holtzhausen A, et al. A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression. Sci Immunol. (2024) 9:eadi4191. doi: 10.1126/sciimmunol.adi4191
106. Chen Z, Liao J, Zhu C, Chang R, Liang H, Ding Z, et al. Exon skipping of ste20-like kinase enhances glycolysis and tumor progression by activating enolase 1–mediated phosphoenolpyruvate production. Cancer Res. (2025) 85:3930–48. doi: 10.1158/0008-5472.CAN-25-0523
107. Sun W, Jia M, Feng Y, and Cheng X. Lactate is a bridge linking glycolysis and autophagy through lactylation. Autophagy. (2023) 19:3240–1. doi: 10.1080/15548627.2023.2246356
108. Xian Z-Y, Liu J-M, Chen Q-K, Chen H-Z, Ye C-J, Xue J, et al. Inhibition of LDHA suppresses tumor progression in prostate cancer. Tumor Biol. (2015) 36:8093–100. doi: 10.1007/s13277-015-3540-x
109. El Khoury A and Papaneophytou C. Flipping the target: evaluating natural LDHA inhibitors for selective LDHB modulation. Molecules. (2025) 30:2923. doi: 10.3390/molecules30142923
110. Ma XM, Geng K, Wang P, Jiang Z, Law BY-K, and Xu Y. MCT4-dependent lactate transport: a novel mechanism for cardiac energy metabolism injury and inflammation in type 2 diabetes mellitus. Cardiovasc Diabetol. (2024) 23:96. doi: 10.1186/s12933-024-02178-2
111. Zhang L, Xin C, Wang S, Zhuo S, Zhu J, Li Z, et al. Lactate transported by MCT1 plays an active role in promoting mitochondrial biogenesis and enhancing TCA flux in skeletal muscle. Sci Adv. (2024) 10:eadn4508. doi: 10.1126/sciadv.adn4508
112. Jia Y, Qiu C, Zhu G, Jin S-W, Lai J-M, Shen Y, et al. Lactate dehydrogenase B deficiency-dependent hyperlactatemia coordinates with necroptosis to worsen septic liver and kidney injuries. Biochem Biophys Res Commun. (2025) 755:151552. doi: 10.1016/j.bbrc.2025.151552
113. Ma M, Liu T, Chen H, Wang Z, Zhou J, Zhou Y, et al. Monocarboxylate transporter 4 inhibition reduces synovial hyperproliferation and metabolic reprogramming under hypoxia in rheumatoid arthritis. Arch Med Res. (2026) 57:103283. doi: 10.1016/j.arcmed.2025.103283
114. Shendy NAM, Bikowitz M, Sigua LH, Zhang Y, Mercier A, Khashana Y, et al. Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition. Nat Commun. (2024) 15:3483. doi: 10.1038/s41467-024-47102-0
115. Marr AR, Halpin M, Corbin DL, Gordon BK, Benrashid S, Whipp EC, et al. Targeting inflammation in Tet2 mutant clonal hematopoiesis via inhibition of Brd4 demonstrates activity in both murine and human models. Blood. (2024) 144:2661. doi: 10.1182/blood-2024-203526
116. Shen H, Qi X, Hu Y, Wang Y, Zhang J, Liu Z, et al. Targeting sirtuins for cancer therapy: epigenetics modifications and beyond. Theranostics. (2024) 14:6726. doi: 10.7150/thno.100667
117. Li T, Xu D, Ruan Z, Zhou J, Sun W, Rao B, et al. Metabolism/immunity dual-regulation thermogels potentiating immunotherapy of glioblastoma through lactate-excretion inhibition and PD-1/PD-L1 blockade. Adv Sci. (2024) 11:2310163. doi: 10.1002/advs.202310163
118. Oh W, Kim AMJ, Dhawan D, Knapp DW, and Lim S-O. Lactic acid inhibits the interaction between PD-L1 protein and PD-L1 antibody in the PD-1/PD-L1 blockade therapy-resistant tumor. Mol Ther. (2025) 33:723–33. doi: 10.1016/j.ymthe.2024.12.044
119. Lin X, Kang K, Chen P, Zeng Z, Li G, Xiong W, et al. Regulatory mechanisms of PD-1/PD-L1 in cancers. Mol Cancer. (2024) 23:108. doi: 10.1186/s12943-024-02023-w
120. Zhang R, Mao G, Tang Y, Li C, Gao Y, Nie W, et al. Inhibition of glycolysis enhances the efficacy of immunotherapy via PDK-mediated upregulation of PD-L1. Cancer Immunol Immunother. (2024) 73:151. doi: 10.1007/s00262-024-03735-0
121. Salminen A. The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases. J Mol Med. (2024) 102:733–50. doi: 10.1007/s00109-024-02444-6
122. Yu X, Yang J, Xu J, Pan H, Wang W, Yu X, et al. Histone lactylation: from tumor lactate metabolism to epigenetic regulation. Int J Biol Sci. (2024) 20:1833. doi: 10.7150/ijbs.91492
123. Wu X, Liu C, Zhang C, Kuai L, Hu S, Jia N, et al. The role of lactate and lactylation in the dysregulation of immune responses in psoriasis. Clin Rev Allergy Immunol. (2025) 68:1–27. doi: 10.1007/s12016-025-09037-2
124. Che X, Zhang Y, Chen X, Xie G, Zhu Y, and Yang X. The lactylation-macrophage interplay: implications for gastrointestinal disease therapeutics. Front Immunol. (2025) 16:1608115. doi: 10.3389/fimmu.2025.1608115
125. Shu M, Lu D, Zhu Z, Yang F, and Ma Z. Insight into the roles of lactylation in macrophages: functions and clinical implications. Clin Sci. (2025) 139:151–69. doi: 10.1042/CS20242737
126. Yang Z, Su W, Zhang Q, Niu L, Feng B, Zhang Y, et al. Lactylation of HDAC1 confers resistance to ferroptosis in colorectal cancer. Adv Sci. (2025) 12:2408845. doi: 10.1002/advs.202408845
127. Duan Y, Zhan H, Wang Q, Li B, Gao H, Liu D, et al. Integrated lactylome characterization reveals the molecular dynamics of protein regulation in gastrointestinal cancers. Adv Sci. (2024) 11:2400227. doi: 10.1002/advs.202400227
128. Diao W, Xu G, and Zhuang J. 23P HDACs inhibitor sensitizes the efficacy of cisplatin via H3K18la mediated transcriptional upregulation of DHRS2 in bladder cancer. Ann Oncol. (2025) 36:S216. doi: 10.1016/j.annonc.2025.08.460
129. Dai R and Sui G. Lactylation modification regulates acute myeloid leukemia pathogenesis and immune microenvironment. Discov Oncol. (2025). doi: 10.1007/s12672-025-03979-x
130. Han R, Chi G, Sun D, Xu Z, Zhou L, and Xu K. Single-cell and spatial transcriptomics reveal lactylation-associated tumor cell clusters and define a prognostic risk model in glioblastoma. BMC Cancer. (2025). doi: 10.1186/s12885-025-15291-6
131. Ren F, Pang X, Jin F, Luan N, Guo H, and Zhu L. Integration of scRNA-seq and bulk RNA-seq to reveal the association and potential molecular mechanisms of metabolic reprogramming regulated by lactylation and chemotherapy resistance in ovarian cancer. Front Immunol. (2025) 16:1513806. doi: 10.3389/fimmu.2025.1513806
Keywords: cancer immunotherapy, epigenetic regulation, histone modi7ication, immunometabolism, lactylation, therapeutic targets, tumor metabolism, tumor microenvironment
Citation: Yang Q, Yang Z and Zhao H (2026) Lactylation in cancer: mechanistic insights, tumor microenvironment, and therapeutic horizons. Front. Immunol. 16:1697008. doi: 10.3389/fimmu.2025.1697008
Received: 01 September 2025; Accepted: 15 December 2025; Revised: 11 December 2025;
Published: 09 January 2026.
Edited by:
Abdullah Saeed, City of Hope National Medical Center, United StatesReviewed by:
Bingteng Xie, Beijing Institute of Technology, ChinaYuexi Gu, ICGEB China Regional Research Centre, China
Copyright © 2026 Yang, Yang and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hai Zhao, emhhbzI3MTQwNEBpY2xvdWQuY29t
†These authors have contributed equally to this work