A Review of Lactate-lactylation in Malignancy: Its Potential in Immunotherapy

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 May 23

PMID 38779665

Authors

Jinhui Zha

Junan Zhang

Jingfen Lu

Guangcheng Zhang

Mengzhan Hua

Weiming Guo

Jing Yang

Gang Fan

Affiliations

Soon will be listed here.

Abstract

Lactic acid was formerly regarded as a byproduct of metabolism. However, extensive investigations into the intricacies of cancer development have revealed its significant contributions to tumor growth, migration, and invasion. Post-translational modifications involving lactate have been widely observed in histone and non-histone proteins, and these modifications play a crucial role in regulating gene expression by covalently attaching lactoyl groups to lysine residues in proteins. This discovery has greatly enhanced our comprehension of lactic acid's involvement in disease pathogenesis. In this article, we provide a comprehensive review of the intricate relationship between lactate and tumor immunity, the occurrence of lactylation in malignant tumors, and the exploitation of targeted lactate-lactylation in tumor immunotherapy. Additionally, we discuss future research directions, aiming to offer novel insights that could inform the investigation, diagnosis, and treatment of related diseases.

Citing Articles

Lactylation modification in cancer: mechanisms, functions, and therapeutic strategies.

Lv M, Huang Y, Chen Y, Ding K Exp Hematol Oncol. 2025; 14(1):32.

PMID: 40057816 PMC: 11889934. DOI: 10.1186/s40164-025-00622-x.

Metabolic crossroads: unravelling immune cell dynamics in gastrointestinal cancer drug resistance.

Suri C, Pande B, Suhasini Sahithi L, Swarnkar S, Khelkar T, Verma H Cancer Drug Resist. 2025; 8:7.

PMID: 40051496 PMC: 11883236. DOI: 10.20517/cdr.2024.164.

Metabolic reprogramming in cancer and senescence.

Zhang Y, Tang J, Jiang C, Yi H, Guang S, Yin G MedComm (2020). 2025; 6(3):e70055.

PMID: 40046406 PMC: 11879902. DOI: 10.1002/mco2.70055.

Implication of protein post translational modifications in gastric cancer.

Song H, Zhang M, Guo C, Guo X, Ma Y, Ma Y Front Cell Dev Biol. 2025; 13:1523958.

PMID: 39968176 PMC: 11833226. DOI: 10.3389/fcell.2025.1523958.

Lactate-induced protein lactylation in cancer: functions, biomarkers and immunotherapy strategies.

Wang W, Wang H, Wang Q, Yu X, Ouyang L Front Immunol. 2025; 15:1513047.

PMID: 39867891 PMC: 11757118. DOI: 10.3389/fimmu.2024.1513047.

References

Mazzio E, Boukli N, Rivera N, Soliman K . Pericellular pH homeostasis is a primary function of the Warburg effect: inversion of metabolic systems to control lactate steady state in tumor cells. Cancer Sci. 2012; 103(3):422-32. PMC: 3294166. DOI: 10.1111/j.1349-7006.2012.02206.x. View

Daneshmandi S, Wegiel B, Seth P . Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma. Cancers (Basel). 2019; 11(4). PMC: 6521327. DOI: 10.3390/cancers11040450. View

Pucino V, Cucchi D, Mauro C . Lactate transporters as therapeutic targets in cancer and inflammatory diseases. Expert Opin Ther Targets. 2018; 22(9):735-743. DOI: 10.1080/14728222.2018.1511706. View

Dangaj D, Bruand M, Grimm A, Ronet C, Barras D, Duttagupta P . Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors. Cancer Cell. 2019; 35(6):885-900.e10. PMC: 6961655. DOI: 10.1016/j.ccell.2019.05.004. View

Yang J, Luo L, Zhao C, Li X, Wang Z, Zeng Z . A Positive Feedback Loop between Inactive VHL-Triggered Histone Lactylation and PDGFRβ Signaling Drives Clear Cell Renal Cell Carcinoma Progression. Int J Biol Sci. 2022; 18(8):3470-3483. PMC: 9134910. DOI: 10.7150/ijbs.73398. View

Faubert B, Li K, Cai L, Hensley C, Kim J, Zacharias L . Lactate Metabolism in Human Lung Tumors. Cell. 2017; 171(2):358-371.e9. PMC: 5684706. DOI: 10.1016/j.cell.2017.09.019. View

Liu T, Han S, Yao Y, Zhang G . Role of Human Monocarboxylate Transporter 1 (hMCT1) and 4 (hMCT4) in Tumor Cells and the Tumor Microenvironment. Cancer Manag Res. 2023; 15:957-975. PMC: 10487743. DOI: 10.2147/CMAR.S421771. View

Yu J, Chai P, Xie M, Ge S, Ruan J, Fan X . Histone lactylation drives oncogenesis by facilitating mA reader protein YTHDF2 expression in ocular melanoma. Genome Biol. 2021; 22(1):85. PMC: 7962360. DOI: 10.1186/s13059-021-02308-z. View

Gao Y, Zhou H, Liu G, Wu J, Yuan Y, Shang A . Tumor Microenvironment: Lactic Acid Promotes Tumor Development. J Immunol Res. 2022; 2022:3119375. PMC: 9207018. DOI: 10.1155/2022/3119375. View

10.

Husain Z, Seth P, Sukhatme V . Tumor-derived lactate and myeloid-derived suppressor cells: Linking metabolism to cancer immunology. Oncoimmunology. 2014; 2(11):e26383. PMC: 3881600. DOI: 10.4161/onci.26383. View

11.

Zhang Y, Peng Q, Zheng J, Yang Y, Zhang X, Ma A . The function and mechanism of lactate and lactylation in tumor metabolism and microenvironment. Genes Dis. 2023; 10(5):2029-2037. PMC: 10363641. DOI: 10.1016/j.gendis.2022.10.006. View

12.

Bottcher M, Baur R, Stoll A, Mackensen A, Mougiakakos D . Linking Immunoevasion and Metabolic Reprogramming in B-Cell-Derived Lymphomas. Front Oncol. 2020; 10:594782. PMC: 7674840. DOI: 10.3389/fonc.2020.594782. View

13.

Jiang J, Huang D, Jiang Y, Hou J, Tian M, Li J . Lactate Modulates Cellular Metabolism Through Histone Lactylation-Mediated Gene Expression in Non-Small Cell Lung Cancer. Front Oncol. 2021; 11:647559. PMC: 8208031. DOI: 10.3389/fonc.2021.647559. View

14.

Sahin U, Tureci O . Personalized vaccines for cancer immunotherapy. Science. 2018; 359(6382):1355-1360. DOI: 10.1126/science.aar7112. View

15.

Xing B, Wang C, Ji F, Zhang X . Synergistically suppressive effects on colorectal cancer cells by combination of mTOR inhibitor and glycolysis inhibitor, Oxamate. Int J Clin Exp Pathol. 2020; 11(9):4439-4445. PMC: 6962984. View

16.

Wang T, Ye Z, Li Z, Jing D, Fan G, Liu M . Lactate-induced protein lactylation: A bridge between epigenetics and metabolic reprogramming in cancer. Cell Prolif. 2023; 56(10):e13478. PMC: 10542650. DOI: 10.1111/cpr.13478. View

17.

Chen M, Cen K, Song Y, Zhang X, Liou Y, Liu P . NUSAP1-LDHA-Glycolysis-Lactate feedforward loop promotes Warburg effect and metastasis in pancreatic ductal adenocarcinoma. Cancer Lett. 2023; 567:216285. DOI: 10.1016/j.canlet.2023.216285. View

18.

Watson M, Vignali P, Mullett S, Overacre-Delgoffe A, Peralta R, Grebinoski S . Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. 2021; 591(7851):645-651. PMC: 7990682. DOI: 10.1038/s41586-020-03045-2. View

19.

Yu J, Shao B, Luo M, Du W, Nie W, Yang J . Irradiated lactic acid-stimulated tumour cells promote the antitumour immunity as a therapeutic vaccine. Cancer Lett. 2019; 469:367-379. DOI: 10.1016/j.canlet.2019.11.018. View

20.

Huang Z, Zhang X, Zhang L, Liu L, Zhang J, Sun Y . STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia. Signal Transduct Target Ther. 2023; 8(1):391. PMC: 10542808. DOI: 10.1038/s41392-023-01605-2. View