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Review Open Access

Effects of lactylation on the hallmarks of cancer (Review)

  • Authors:
    • Yujie Fan
    • Zhangda Chen
    • Jiaxin Li
    • Lidan Ding
  • View Affiliations / Copyright

    Affiliations: Department of General Surgery, Wenzhou Medical University Lishui Hospital and Lishui City People's Hospital, Lishui, Zhejiang 323000, P.R. China, Department of Clinical Nutrition, Wenzhou Medical University Lishui Hospital and Lishui City People's Hospital, Lishui, Zhejiang 323000, P.R. China
    Copyright: © Fan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 492
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    Published online on: August 20, 2025
       https://doi.org/10.3892/ol.2025.15238
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Abstract

Lactylation, an emerging metabolism‑dependent post‑translational modification, serves as a core mechanism linking metabolic reprogramming with epigenetic regulation in establishing the multifaceted hallmarks of cancer. The present review systematically elucidates how lactylation dynamically regulates the functions of both histone and non‑histone proteins, driving the acquisition of classical cancer hallmarks including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, activation of invasion and metastasis and replicative immortality. Furthermore, lactylation is intricately involved in enabling the emerging hallmarks of cancer, such as the maintenance of genome instability, shaping of a pro‑­inflammatory tumor microenvironment (TME), immune escape, metabolic reprogramming, unlocking phenotypic plasticity and non‑mutational epigenetic reprogramming. By reshaping the interaction networks among cancer, stromal and immune cells within the TME, lactylation promotes the formation of an immunosuppressive microenvironment and enhances resistance to therapy. Targeting lactylation regulatory pathways (such as lactate dehydrogenase A inhibitors, monocarboxylate transporter inhibitors and delactylase activators) can reverse key hallmark phenotypes, highlighting novel therapeutic avenues for the development of precision anticancer strategies based on interrupting metabolic‑­epigenetic crosstalk.
View Figures

Figure 1

In the TME, lactate polarizes TAMs to
the M2 phenotype through histone lactylation. Lactate-treated Th17
cells markedly reduce IL-17A and upregulate Foxp3. The high-energy
metabolites (such as lactate and pyruvate) produced by CAFs via
aerobic glycolysis are translocated into adjacent epithelial cancer
cells. DL can promote the transformation of M2 to M1 macrophages by
regulating the lactylation of macrophages, specifically through the
inhibition of the PI3K/Akt pathway and the activation of the NF-κB
pathway. PCSK9 affect the polarization of TAMs in colon cancer by
regulating MIF and lactate levels. Higher glycolysis, hypoxia and
the Warburg effect elevate lactate levels and promote tumor growth,
evasion and metastasis. In cancer cells, lactate produced from
glucose and exogenous lactate is further metabolized to produce
lactyl-CoA, which can enter and exit the nucleus. p300, as a writer
of lactylations, can add lactyl groups to lysine residues of
histones or non-histone proteins to form lactylations, while
erasers HDAC1-3 remove lactate modification motifs from histones or
non-histone proteins and restore them to their original state. MIF,
macrophage migration inhibitory factor; DL, D-lactic acid; TCA
cycle, tricarboxylic acid cycle; TME, tumor microenvironment; PDH,
pyruvate dehydrogenase; LDH, lactate dehydrogenase; PCSK9,
proprotein convertase subtilisin/kexin type 9; CAFs,
cancer-associated fibroblasts; TAMs, tumor-associated macrophages;
HDAC, histone deacetylase.

Figure 2

Relationship between lactylation and
cancer hallmarks. The hallmarks of cancer are pivotal
characteristics employed in cancer research to distinguish tumor
cells from normal cells. MHC, major histocompatibility complex;
TCR, T-cell receptor.

Figure 3

Schematic overview depicting
lactylation as a metabolic-epigenetic hub that integrates tumor
metabolism, immune evasion and cancer hallmark acquisition within
the tumor microenvironment. LPS, lipopolysaccharide; Treg,
regulatory T cells; TGF-β, transforming growth factor β; M1,
classically activated (pro-inflammatory) macrophages; M2,
alternatively activated (anti-inflammatory) macrophages; LSD1,
lysine-specific histone demethylase 1; YY1, yin yang 1
(transcription factor); XRCC1, X-ray repair cross-complementing
protein 1.
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Copy and paste a formatted citation
Spandidos Publications style
Fan Y, Chen Z, Li J and Ding L: Effects of lactylation on the hallmarks of cancer (Review). Oncol Lett 30: 492, 2025.
APA
Fan, Y., Chen, Z., Li, J., & Ding, L. (2025). Effects of lactylation on the hallmarks of cancer (Review). Oncology Letters, 30, 492. https://doi.org/10.3892/ol.2025.15238
MLA
Fan, Y., Chen, Z., Li, J., Ding, L."Effects of lactylation on the hallmarks of cancer (Review)". Oncology Letters 30.5 (2025): 492.
Chicago
Fan, Y., Chen, Z., Li, J., Ding, L."Effects of lactylation on the hallmarks of cancer (Review)". Oncology Letters 30, no. 5 (2025): 492. https://doi.org/10.3892/ol.2025.15238
Copy and paste a formatted citation
x
Spandidos Publications style
Fan Y, Chen Z, Li J and Ding L: Effects of lactylation on the hallmarks of cancer (Review). Oncol Lett 30: 492, 2025.
APA
Fan, Y., Chen, Z., Li, J., & Ding, L. (2025). Effects of lactylation on the hallmarks of cancer (Review). Oncology Letters, 30, 492. https://doi.org/10.3892/ol.2025.15238
MLA
Fan, Y., Chen, Z., Li, J., Ding, L."Effects of lactylation on the hallmarks of cancer (Review)". Oncology Letters 30.5 (2025): 492.
Chicago
Fan, Y., Chen, Z., Li, J., Ding, L."Effects of lactylation on the hallmarks of cancer (Review)". Oncology Letters 30, no. 5 (2025): 492. https://doi.org/10.3892/ol.2025.15238
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