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Review Open Access

Research progress of lactylation modification in tumors (Review)

  • Authors:
    • Shi-Chao Fang
    • Zhi-Zhou Shi
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    Affiliations: Laboratory of Molecular Neurobiology, Faculty of Medicine, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China
    Copyright: © Fang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 233
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    Published online on: July 6, 2026
       https://doi.org/10.3892/etm.2026.13229
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Abstract

Lactic acid was once thought to be only a metabolic product of glycolysis. An increasing number of studies, however, have reported that lactic acid produced by glycolysis is a multifunctional signaling molecule that not only serves as an essential energy source, signaling molecule and immunomodulatory molecule but also controls metabolism, the immune response and intercellular communication. It has been discovered that lactylation is a posttranslational modification of proteins that regulates and creates an acidic tumor microenvironment, directly regulates gene expression and promotes the recruitment and management of immune signaling molecules, among other processes, to promote tumor survival and progression. The lactylation of histones and non‑histone proteins, which is regulated by different mechanisms, is a notable subject of current research on the tumor microenvironment and tumor progression. The present review covered the discovery of lactylation and the research advances on the role of lactylation in metabolism, immunity, metastasis and cell proliferation across different tumors. These findings open up the possibility for in‑depth investigation of the role of lactylation in tumors.
View Figures

Figure 1

Tumor cells produce lactic acid
through the Warburg effect. The produced lactic acid can serve as a
substrate for lactylation modification, promoting the lactylation
of histones and non-histones during cell proliferation, metastasis,
immunity and metabolism. AXIN1, axis inhibition protein 1; PEKP,
phosphofructokinase, platelet; APOC2, Apolipoprotein C2; NUSAP1,
nucleolar and spindle-associated protein 1; YAP, yes-associated
protein; TEAD, TEA domain; NCL, nucleocapsid; CENPA, centromeric
protein A; SHMT2, serine hydroxymethyltransferase-2; H3K18, histone
H3 lysine 18; H4K5, histone H4 lysine 5; H3K9, histone H3 lysine 9;
H4K8, histone H4 lysine 8; H3K56, histone H3 lysine 56; H4K12, H4
lysine 12.

Figure 2

Histone and non-histone lactylation
in tumor immunity. Lactate accumulation in TME reshapes the
immunomicroenvironment. IL-11, interlukin-11; H3K9, histone H3
lysine 9; JAK1, janus kinase 1; STAT3, signal transducer and
activator of transcription 3; H3K18, histone H3 lysine 18; PD-L1,
Programmed death-ligand 1; STAT5, signal transducer and activator
of transcription 5; H4K5, histone H4 lysine 5; VCAM1, vascular cell
adhesion molecule-1; CXCL1, C-X-C motif ligand 1; SMAD3, small
mother against decapentaplegic family member 3; Rig-1, retinoic
acid-inducible gene I; Nlrp3, nod-like receptor protein 3; APOC2,
apolipoprotein C2; METTL3, methyltransferase-like 3; TME, tumor
microenvironment; Tregs, regulatory T cells; FFAS, free fatty
acids; MSN, moesin; CC, cervical cancer; PDAC, pancreatic ductal
adenocarcinoma; NSCLC, non-small cell lung cancer; GC, gastric
cancer; GBM, glioblastoma; HNSCC, head and neck squamous cell
carcinoma; AML, acute myeloid leukemia; CRC, colorectal cancer.

Figure 3

Histone and non-histone lactylation
in tumor metabolism. The tumor metabolism was regulated by H3K18la
and the lactylation of NUSAP1, YAP and GPC3. NUSAP1, nucleolar and
spindle-associated protein 1; LDHA, lactate dehydrogenase A; PFKP,
phosphofructokinase, platelet; YAP, yes-associated protein; PFKFB4,
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4; H3K18,
histone H3 lysine 18; LDHA, lactate dehydrogenase A; ENO1, enolase
1; HIF-1α, hypoxia-inducible factor-1α; GPC3, glypican-3; CRC,
colorectal cancer; PCa, prostate cancer; BC, bladder cancer; PDAC,
pancreatic ductal adenocarcinoma; HCC, hepatocellular
carcinoma.

Figure 4

Histone and non-histone lactylation
in tumor cell proliferation. Protein lactylation promotes the
proliferation of tumor cells by regulating PI3K/Akt/VEGFA,
METTL3/c-Myc/NF-kB, and CENPA-YY1-CCND1/NRP2 signaling pathways.
H3K9, histone H3 lysine 9; LAMC2, laminin γ 2; CENPA, centromeric
protein A; YY1, yin yang 1; CCND1, cyclin D1; NRP2, neuropilin-2;
METTL3, methyltransferase-like 3; NF-κb, nuclear factor κB; H3K18,
histone H3 lysine 18; VEGFA, vascular endothelial growth factor A;
ESCC, esophageal squamous cell carcinoma; HCC, hepatocellular
carcinoma; CRC, colorectal cancer; EMT, epithelial-mesenchymal
transition.

Figure 5

Histone and non-histone lactylation
in tumor cell metastasis. Protein lactylation enhances tumor cell
metastasis by mediating several pathways such as
GLUT3/LDHA/H3K9la/H3K18la/H3K56la, KCNK1/LDHA/H3K18la, and
RHOF/c-Myc/PKM2/Snail1. GLUT3, glucose transporter protein 3; LDHA,
lactate dehydrogenase A; H3K9, histone H3 lysine 9; H3K18, histone
H3 lysine 18; H3K56, histone H3 lysine 56; H4K8, histone H4 lysine
8; SHMT2, serine hydroxymethyltransferase-2; MTHFD1L,
methylenetetrahydrofolate dehydrogenase 1 like; KCNK1, potassium
two pore domain channel subfamily K member 1; LCN2, lipocalin 2;
RHOF, Rho GTPase Rif; ESM1, endothelial cell-specific molecule 1;
EMT, epithelial-mesenchymal transition; GC, gastric cancer; BC,
bladder cancer; CRC, colorectal cancer; HCC, hepatocellular
carcinoma; PC, pancreatic cancer; EC, esophageal cancer.
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Copy and paste a formatted citation
Spandidos Publications style
Fang S and Shi Z: Research progress of lactylation modification in tumors (Review). Exp Ther Med 32: 233, 2026.
APA
Fang, S., & Shi, Z. (2026). Research progress of lactylation modification in tumors (Review). Experimental and Therapeutic Medicine, 32, 233. https://doi.org/10.3892/etm.2026.13229
MLA
Fang, S., Shi, Z."Research progress of lactylation modification in tumors (Review)". Experimental and Therapeutic Medicine 32.3 (2026): 233.
Chicago
Fang, S., Shi, Z."Research progress of lactylation modification in tumors (Review)". Experimental and Therapeutic Medicine 32, no. 3 (2026): 233. https://doi.org/10.3892/etm.2026.13229
Copy and paste a formatted citation
x
Spandidos Publications style
Fang S and Shi Z: Research progress of lactylation modification in tumors (Review). Exp Ther Med 32: 233, 2026.
APA
Fang, S., & Shi, Z. (2026). Research progress of lactylation modification in tumors (Review). Experimental and Therapeutic Medicine, 32, 233. https://doi.org/10.3892/etm.2026.13229
MLA
Fang, S., Shi, Z."Research progress of lactylation modification in tumors (Review)". Experimental and Therapeutic Medicine 32.3 (2026): 233.
Chicago
Fang, S., Shi, Z."Research progress of lactylation modification in tumors (Review)". Experimental and Therapeutic Medicine 32, no. 3 (2026): 233. https://doi.org/10.3892/etm.2026.13229
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