Thanks to visit codestin.com
Credit goes to link.springer.com

Skip to main content
Springer Nature Link
Log in

Lactate and lactylation in tumor immunity

  • Review
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

Abstract

The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate’s role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate’s importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from £29.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  1. Warburg O. On the origin of cancer cells. Science 1956; 123(3191): 309–314

    Article  CAS  PubMed  Google Scholar 

  2. Lee TY. Lactate: a multifunctional signaling molecule. Yeungnam Univ J Med 2021; 38(3): 183–193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab 2020; 2(2): 127–129

    Article  PubMed  Google Scholar 

  4. Xia L, Oyang L, Lin J, Tan S, Han Y, Wu N, Yi P, Tang L, Pan Q, Rao S, Liang J, Tang Y, Su M, Luo X, Yang Y, Shi Y, Wang H, Zhou Y, Liao Q. The cancer metabolic reprogramming and immune response. Mol Cancer 2021; 20(1): 28

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bilotta MT, Antignani A, Fitzgerald DJ. Managing the TME to improve the efficacy of cancer therapy. Front Immunol 2022; 13: 954992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tiwari A, Trivedi R, Lin SY. Tumor microenvironment: barrier or opportunity towards effective cancer therapy. J Biomed Sci 2022; 29(1): 83

    Article  PubMed  PubMed Central  Google Scholar 

  7. Brooks GA. The science and translation of lactate shuttle theory. Cell Metab 2018; 27(4): 757–785

    Article  CAS  PubMed  Google Scholar 

  8. Brown TP, Ganapathy V. Lactate/GPR81 signaling and proton motive force in cancer: role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther 2020; 206: 107451

    Article  CAS  PubMed  Google Scholar 

  9. Laroche S, Stil A, Germain P, Cherif H, Chemtob S, Bouchard JF. Participation of L-lactate and its receptor HCAR1/GPR81 in neurovisual development. Cells 2021; 10(7): 1640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sun Z, Han Y, Song S, Chen T, Han Y, Liu Y. Activation of GPR81 by lactate inhibits oscillatory shear stress-induced endothelial inflammation by activating the expression of KLF2. IUBMB Life 2019; 71(12): 2010–2019

    Article  CAS  PubMed  Google Scholar 

  11. Roland CL, Arumugam T, Deng D, Liu SH, Philip B, Gomez S, Burns WR, Ramachandran V, Wang H, Cruz-Monserrate Z, Logsdon CD. Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Res 2014; 74(18): 5301–5310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Longhitano L, Forte S, Orlando L, Grasso S, Barbato A, Vicario N, Parenti R, Fontana P, Amorini AM, Lazzarino G, Li Volti G, Di Rosa M, Liso A, Tavazzi B, Lazzarino G, Tibullo D. The crosstalk between GPR81/IGFBP6 promotes breast cancer progression by modulating lactate metabolism and oxidative stress. Antioxidants 2022; 11(2): 275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yu J, Du Y, Liu C, Xie Y, Yuan M, Shan M, Li N, Liu C, Wang Y, Qin J. Low GPR81 in ER+ breast cancer cells drives tamoxifen resistance through inducing PPARα-mediated fatty acid oxidation. Life Sci 2024; 350: 122763

    Article  CAS  PubMed  Google Scholar 

  14. Feng J, Yang H, Zhang Y, Wei H, Zhu Z, Zhu B, Yang M, Cao W, Wang L, Wu Z. Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene 2017; 36(42): 5829–5839

    Article  CAS  PubMed  Google Scholar 

  15. Xie Q, Zhu Z, He Y, Zhang Z, Zhang Y, Wang Y, Luo J, Peng T, Cheng F, Gao J, Cao Y, Wei H, Wu Z. A lactate-induced Snail/STAT3 pathway drives GPR81 expression in lung cancer cells. Biochim Biophys Acta Mol Basis Dis 2020; 1866(1): 165576

    Article  CAS  PubMed  Google Scholar 

  16. Guo X, Wan P, Shen W, Sun M, Peng Z, Liao Y, Huang Y, Liu R. Fusobacterium periodonticum BCT protein targeting glucose metabolism to promote the epithelial-mesenchymal transition of esophageal cancer cells by lactic acid. J Transl Med 2024; 22(1): 401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gong C, Yang M, Long H, Liu X, Xu Q, Qiao L, Dong H, Liu Y, Li S. IL-6-driven autocrine lactate promotes immune escape of uveal melanoma. Invest Ophthalmol Vis Sci 2024; 65(3): 37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu X, Li S, Cui Q, Guo B, Ding W, Liu J, Quan L, Li X, Xie P, Jin L, Sheng Y, Chen W, Wang K, Zeng F, Qiu Y, Liu C, Zhang Y, Lv F, Hu X, Xiao RP. Activation of GPR81 by lactate drives tumour-induced cachexia. Nat Metab 2024; 6(4): 708–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen S, Zhou X, Yang X, Li W, Li S, Hu Z, Ling C, Shi R, Liu J, Chen G, Song N, Jiang X, Sui X, Gao Y. Dual blockade of lactate/GPR81 and PD-1/PD-L1 pathways enhances the antitumor effects of metformin. Biomolecules 2021; 11(9): 1373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang X, Lu Y, Hang J, Zhang J, Zhang T, Huo Y, Liu J, Lai S, Luo D, Wang L, Hua R, Lin Y. Lactate-modulated immunosuppression of myeloid-derived suppressor cells contributes to the radioresistance of pancreatic cancer. Cancer Immunol Res 2020; 8(11): 1440–1451

    Article  CAS  PubMed  Google Scholar 

  21. Ranganathan P, Shanmugam A, Swafford D, Suryawanshi A, Bhattacharjee P, Hussein MS, Koni PA, Prasad PD, Kurago ZB, Thangaraju M, Ganapathy V, Manicassamy S. GPR81, a cell-surface receptor for lactate, regulates intestinal homeostasis and protects mice from experimental colitis. J Immunol 2018; 200(5): 1781–1789

    Article  CAS  PubMed  Google Scholar 

  22. Jeninga EH, Bugge A, Nielsen R, Kersten S, Hamers N, Dani C, Wabitsch M, Berger R, Stunnenberg HG, Mandrup S, Kalkhoven E. Peroxisome proliferator-activated receptor gamma regulates expression of the anti-lipolytic G-protein-coupled receptor 81 (GPR81/Gpr81). J Biol Chem 2009; 284(39): 26385–26393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Raychaudhuri D, Bhattacharya R, Sinha BP, Liu CSC, Ghosh AR, Rahaman O, Bandopadhyay P, Sarif J, D’Rozario R, Paul S, Das A, Sarkar DK, Chattopadhyay S, Ganguly D. Lactate induces pro-tumor reprogramming in intratumoral plasmacytoid dendritic cells. Front Immunol 2019; 10: 1878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hoque R, Farooq A, Ghani A, Gorelick F, Mehal WZ. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology 2014; 146(7): 1763–1774

    Article  CAS  PubMed  Google Scholar 

  25. Brown TP, Bhattacharjee P, Ramachandran S, Sivaprakasam S, Ristic B, Sikder MOF, Ganapathy V. The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment. Oncogene 2020; 39(16): 3292–3304

    Article  CAS  PubMed  Google Scholar 

  26. Su J, Mao X, Wang L, Chen Z, Wang W, Zhao C, Li G, Guo W, Hu Y. Lactate/GPR81 recruits regulatory T cells by modulating CX3CL1 to promote immune resistance in a highly glycolytic gastric cancer. OncoImmunology 2024; 13(1): 2320951

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zeng Z, Mukherjee A, Varghese AP, Yang XL, Chen S, Zhang H. Roles of G protein-coupled receptors in inflammatory bowel disease. World J Gastroenterol 2020; 26(12): 1242–1261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Justus CR, Dong L, Yang LV. Acidic tumor microenvironment and pH-sensing G protein-coupled receptors. Front Physiol 2013; 4: 354

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kern K, Schäfer SMG, Cohnen J, Pierre S, Osthues T, Tarighi N, Hohmann S, Ferreiros N, Brüne B, Weigert A, Geisslinger G, Sisignano M, Scholich K. The G2A receptor controls polarization of macrophage by determining their localization within the inflamed tissue. Front Immunol 2018; 9: 2261

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chen P, Zuo H, Xiong H, Kolar MJ, Chu Q, Saghatelian A, Siegwart DJ, Wan Y. Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis. Proc Natl Acad Sci USA 2017; 114(3): 580–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cheng WY, Huynh H, Chen P, Peña-Llopis S, Wan Y. Macrophage PPARγ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone. eLife 2016; 5: e18501

    Article  PubMed  PubMed Central  Google Scholar 

  32. Vadevoo SMP, Gunassekaran GR, Lee C, Lee N, Lee J, Chae S, Park JY, Koo J, Lee B. The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages. Proc Natl Acad Sci USA 2021; 118(37): e2102434118

    Article  PubMed  PubMed Central  Google Scholar 

  33. Liu X, Wang X, Zhang J, Tian T, Ning Y, Chen Y, Li G, Cui Z. Myc-mediated inhibition of HIF1a degradation promotes M2 macrophage polarization and impairs CD8 T cell function through lactic acid secretion in ovarian cancer. Int Immunopharmacol 2024; 141: 112876

    Article  CAS  PubMed  Google Scholar 

  34. Liu Y, Jiang C, Xu C, Gu L. Systematic analysis of integrated bioinformatics to identify upregulated THBS2 expression in colorectal cancer cells inhibiting tumour immunity through the HIF1A/Lactic Acid/GPR132 pathway. Cancer Cell Int 2023; 23(1): 253

    Article  PubMed  PubMed Central  Google Scholar 

  35. Le LQ, Kabarowski JH, Weng Z, Satterthwaite AB, Harvill ET, Jensen ER, Miller JF, Witte ON. Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset autoimmune syndrome. Immunity 2001; 14(5): 561–571

    Article  CAS  PubMed  Google Scholar 

  36. Nii T, Prabhu VV, Ruvolo V, Madhukar N, Zhao R, Mu H, Heese L, Nishida Y, Kojima K, Garnett MJ, McDermott U, Benes CH, Charter N, Deacon S, Elemento O, Allen JE, Oster W, Stogniew M, Ishizawa J, Andreeff M. Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia. Leukemia 2019; 33(12): 2805–2816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chauhan AS, Zhuang L, Gan B. Antagonism between antiviral signaling and glycolysis. Trends Endocrinol Metab 2019; 30(9): 571–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang W, Wang G, Xu ZG, Tu H, Hu F, Dai J, Chang Y, Chen Y, Lu Y, Zeng H, Cai Z, Han F, Xu C, Jin G, Sun L, Pan BS, Lai SW, Hsu CC, Xu J, Chen ZZ, Li HY, Seth P, Hu J, Zhang X, Li H, Lin HK. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 2019; 178(1): 176–189.e15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhou L, He R, Fang P, Li M, Yu H, Wang Q, Yu Y, Wang F, Zhang Y, Chen A, Peng N, Lin Y, Zhang R, Trilling M, Broering R, Lu M, Zhu Y, Liu S. Hepatitis B virus rigs the cellular metabolome to avoid innate immune recognition. Nat Commun 2021; 12(1): 98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li H, Lin C, Qi W, Sun Z, Xie Z, Jia W, Ning Z. Senecavirus A-induced glycolysis facilitates virus replication by promoting lactate production that attenuates the interaction between MAVS and RIG-I. PLoS Pathog 2023; 19(5): e1011371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Li S, Mo J, Fang Y, Chen X, Chen M, Wang S, Li H, Ning Z. Macrophage migration inhibitory factor facilitates replication of Senecavirus A by enhancing the glycolysis via hypoxia inducible factor 1 alpha. Int J Biol Macromol 2024; 281: 136197

    Article  CAS  PubMed  Google Scholar 

  42. Yu A, Fu L, Jing L, Wang Y, Ma Z, Zhou X, Yang R, Liu J, Hu J, Feng W, Yang T, Chen Z, Zu X, Chen W, Chen J, Luo J. Methionine-driven YTHDF1 expression facilitates bladder cancer progression by attenuating RIG-I-modulated immune responses and enhancing the eIF5B-PD-L1 axis. Cell Death Differ 2025; 32(4): 776–791

    Article  CAS  PubMed  Google Scholar 

  43. Huang T, Ao X, Liu J, Sun C, Dong Y, Yin X, Zhang Y, Wang X, Li W, Cao J, Pan F, Hu Z, Guo Z, He L. m6A methyltransferase METTL3 promotes non-small-cell lung carcinoma progression by inhibiting the RIG-I-MAVS innate immune pathway. Transl Oncol 2025; 51: 102230

    Article  CAS  PubMed  Google Scholar 

  44. Miranda A, Pattnaik S, Hamilton PT, Fuss MA, Kalaria S, Laumont CM, Smazynski J, Mesa M, Banville A, Jiang X, Jenkins R, Cañadas I, Nelson BH. N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma. Sci Adv 2024; 10(20): eadj5428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhao X, Zhang Z, Wang J, Feng S, Jiang L, Chen L, Lei K, Wang T. Ro 90–7501 suppresses colon cancer progression by inducing immunogenic cell death and promoting RIG-1-mediated autophagy. Int Immunopharmacol 2024; 143: 113631

    Article  CAS  PubMed  Google Scholar 

  46. Huang W, Zhu Q, Shi Z, Tu Y, Li Q, Zheng W, Yuan Z, Li L, Zu X, Hao Y, Chu B, Jiang Y. Dual inhibitors of DNMT and HDAC induce viral mimicry to induce antitumour immunity in breast cancer. Cell Death Discov 2024; 10(1): 143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhang Q, Jiang L, Wang W, Huber AK, Valvo VM, Jungles KM, Holcomb EA, Pearson AN, The S, Wang Z, Parsels LA, Parsels JD, Wahl DR, Rao A, Sahai V, Lawrence TS, Green MD, Morgan MA. Potentiating the radiation-induced type I interferon antitumoral immune response by ATM inhibition in pancreatic cancer. JCI Insight 2024; 9(6): e168824

    PubMed  PubMed Central  Google Scholar 

  48. Moreno V, Calvo E, Middleton MR, Barlesi F, Gaudy-Marqueste C, Italiano A, Romano E, Marabelle A, Chartash E, Dobrenkov K, Zhou H, Connors EC, Zhang Y, Wermke M. Treatment with a retinoic acid-inducible gene I (RIG-I) agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: results from two phase 1 studies. Cancer Immunol Immunother 2022; 71(12): 2985–2998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kes MMG, Van den Bossche J, Griffioen AW, Huijbers EJM. Oncometabolites lactate and succinate drive pro-angiogenic macrophage response in tumors. Biochim Biophys Acta Rev Cancer 2020; 1874(2): 188427

    Article  CAS  PubMed  Google Scholar 

  50. Liu X, Zhang Y, Li W, Zhou X. Lactylation, an emerging hallmark of metabolic reprogramming: current progress and open challenges. Front Cell Dev Biol 2022; 10: 972020

    Article  PubMed  PubMed Central  Google Scholar 

  51. Parks SK, Pouysségur J. Targeting pH regulating proteins for cancer therapy—progress and limitations. Semin Cancer Biol 2017; 43: 66–73

    Article  CAS  PubMed  Google Scholar 

  52. Rabinowitz JD, Enerbäck S. Lactate: the ugly duckling of energy metabolism. Nat Metab 2020; 2(7): 566–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wilde L, Roche M, Domingo-Vidal M, Tanson K, Philp N, Curry J, Martinez-Outschoorn U. Metabolic coupling and the reverse Warburg effect in cancer: implications for novel biomarker and anticancer agent development. Semin Oncol 2017; 44(3): 198–203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li X, Yang Y, Zhang B, Lin X, Fu X, An Y, Zou Y, Wang JX, Wang Z, Yu T. Lactate metabolism in human health and disease. Signal Transduct Target Ther 2022; 7(1): 305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Price NT, Jackson VN, Halestrap AP. Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past. Biochem J 1998; 329(2): 321–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Brooks GA, Brown MA, Butz CE, Sicurello JP, Dubouchaud H. Cardiac and skeletal muscle mitochondria have a monocarboxylate transporter MCT1. J Appl Physiol (1985) 1999; 87(5): 1713–1718

    Article  CAS  PubMed  Google Scholar 

  57. Byun JK. Tumor lactic acid: a potential target for cancer therapy. Arch Pharm Res 2023; 46(2): 90–110

    Article  CAS  PubMed  Google Scholar 

  58. Luo F, Zou Z, Liu X, Ling M, Wang Q, Wang Q, Lu L, Shi L, Liu Y, Liu Q, Zhang A. Enhanced glycolysis, regulated by HIF-1α via MCT-4, promotes inflammation in arsenite-induced carcinogenesis. Carcinogenesis 2017; 38(6): 615–626

    Article  CAS  PubMed  Google Scholar 

  59. Bovenzi CD, Hamilton J, Tassone P, Johnson J, Cognetti DM, Luginbuhl A, Keane WM, Zhan T, Tuluc M, Bar-Ad V, Martinez-Outschoorn U, Curry JM. Prognostic indications of elevated MCT4 and CD147 across cancer types: a meta-analysis. BioMed Res Int 2015; 2015: 242437

    Article  PubMed  PubMed Central  Google Scholar 

  60. Javaeed A, Ghauri SK. MCT4 has a potential to be used as a prognostic biomarker—a systematic review and meta-analysis. Oncol Rev 2019; 13(2): 403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Baek G, Tse YF, Hu Z, Cox D, Buboltz N, McCue P, Yeo CJ, White MA, DeBerardinis RJ, Knudsen ES, Witkiewicz AK. MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell Rep 2014; 9(6): 2233–2249

    Article  CAS  PubMed  Google Scholar 

  62. Kuo TC, Huang KY, Yang SC, Wu S, Chung WC, Chang YL, Hong TM, Wang SP, Chen HY, Hsiao TH, Yang PC. Monocarboxylate transporter 4 is a therapeutic target in non-small cell lung cancer with aerobic glycolysis preference. Mol Ther Oncolytics 2020; 18: 189–201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang ZH, Peng WB, Zhang P, Yang XP, Zhou Q. Lactate in the tumour microenvironment: from immune modulation to therapy. EBioMedicine 2021; 73: 103627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, Kastenberger M, Bogdan C, Schleicher U, Mackensen A, Ullrich E, Fichtner-Feigl S, Kesselring R, Mack M, Ritter U, Schmid M, Blank C, Dettmer K, Oefner PJ, Hoffmann P, Walenta S, Geissler EK, Pouyssegur J, Villunger A, Steven A, Seliger B, Schreml S, Haferkamp S, Kohl E, Karrer S, Berneburg M, Herr W, Mueller-Klieser W, Renner K, Kreutz M. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 2016; 24(5): 657–671

    Article  CAS  PubMed  Google Scholar 

  65. Mendler AN, Hu B, Prinz PU, Kreutz M, Gottfried E, Noessner E. Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int J Cancer 2012; 131(3): 633–640

    Article  CAS  PubMed  Google Scholar 

  66. Elia I, Rowe JH, Johnson S, Joshi S, Notarangelo G, Kurmi K, Weiss S, Freeman GJ, Sharpe AH, Haigis MC. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells. Cell Metab 2022; 34(8): 1137–1150.e6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D’Acquisto F, Bland EJ, Bombardieri M, Pitzalis C, Perretti M, Marelli-Berg FM, Mauro C. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol 2015; 13(7): e1002202

    Article  PubMed  PubMed Central  Google Scholar 

  68. Shan T, Chen S, Chen X, Wu T, Yang Y, Li S, Ma J, Zhao J, Lin W, Li W, Cui X, Kang Y. M2-TAM subsets altered by lactic acid promote T-cell apoptosis through the PD-L1/PD-1 pathway. Oncol Rep 2020; 44: 1885–1894

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007; 109(9): 3812–3819

    Article  CAS  PubMed  Google Scholar 

  70. Wang D, Quiros J, Mahuron K, Pai CC, Ranzani V, Young A, Silveria S, Harwin T, Abnousian A, Pagani M, Rosenblum MD, Van Gool F, Fong L, Bluestone JA, DuPage M. Targeting EZH2 reprograms intratumoral regulatory T cells to enhance cancer immunity. Cell Rep 2018; 23(11): 3262–3274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wu Q, Zhou W, Yin S, Zhou Y, Chen T, Qian J, Su R, Hong L, Lu H, Zhang F, Xie H, Zhou L, Zheng S. Blocking triggering receptor expressed on myeloid cells-1-positive tumor-associated macrophages induced by hypoxia reverses immunosuppression and anti-programmed cell death ligand 1 resistance in liver cancer. Hepatology 2019; 70(1): 198–214

    Article  CAS  PubMed  Google Scholar 

  72. Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, Ito D, Fujii R, Watanabe S, Sai A, Fukuoka S, Sugiyama E, Watanabe G, Owari T, Nishinakamura H, Sugiyama D, Maeda Y, Kawazoe A, Yukami H, Chida K, Ohara Y, Yoshida T, Shinno Y, Takeyasu Y, Shirasawa M, Nakama K, Aokage K, Suzuki J, Ishii G, Kuwata T, Sakamoto N, Kawazu M, Ueno T, Mori T, Yamazaki N, Tsuboi M, Yatabe Y, Kinoshita T, Doi T, Shitara K, Mano H, Nishikawa H. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022; 40(2): 201–218.e9

    Article  CAS  PubMed  Google Scholar 

  73. Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ 3rd, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 2017; 25(6): 1282–1293.e7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ding R, Yu X, Hu Z, Dong Y, Huang H, Zhang Y, Han Q, Ni ZY, Zhao R, Ye Y, Zou Q. Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells. Immunity 2024; 57(3): 528–540.e6

    Article  CAS  PubMed  Google Scholar 

  75. Watson MJ, Vignali PDA, Mullett SJ, Overacre-Delgoffe AE, Peralta RM, Grebinoski S, Menk AV, Rittenhouse NL, DePeaux K, Whetstone RD, Vignali DAA, Hand TW, Poholek AC, Morrison BM, Rothstein JD, Wendell SG, Delgoffe GM. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 2021; 591(7851): 645–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lopez Krol A, Nehring HP, Krause FF, Wempe A, Raifer H, Nist A, Stiewe T, Bertrams W, Schmeck B, Luu M, Leister H, Chung HR, Bauer UM, Adhikary T, Visekruna A. Lactate induces metabolic and epigenetic reprogramming of pro-inflammatory Th17 cells. EMBO Rep 2022; 23(12): e54685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Comito G, Iscaro A, Bacci M, Morandi A, Ippolito L, Parri M, Montagnani I, Raspollini MR, Serni S, Simeoni L, Giannoni E, Chiarugi P. Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis. Oncogene 2019; 38(19): 3681–3695

    Article  CAS  PubMed  Google Scholar 

  78. Xia H, Wang W, Crespo J, Kryczek I, Li W, Wei S, Bian Z, Maj T, He M, Liu RJ, He Y, Rattan R, Munkarah A, Guan JL, Zou W. Suppression of FIP200 and autophagy by tumor-derived lactate promotes naïve T cell apoptosis and affects tumor immunity. Sci Immunol 2017; 2(17): eaan4631

    Article  PubMed  PubMed Central  Google Scholar 

  79. Krasnova Y, Putz EM, Smyth MJ, Souza-Fonseca-Guimaraes F. Bench to bedside: NK cells and control of metastasis. Clin Immunol 2017; 177: 50–59

    Article  CAS  PubMed  Google Scholar 

  80. Terrén I, Orrantia A, Vitallé J, Zenarruzabeitia O, Borrego F. NK cell metabolism and tumor microenvironment. Front Immunol 2019; 10: 2278

    Article  PubMed  PubMed Central  Google Scholar 

  81. Husain Z, Huang Y, Seth P, Sukhatme VP. Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J Immunol 2013; 191(3): 1486–1495

    Article  CAS  PubMed  Google Scholar 

  82. Husain Z, Seth P, Sukhatme VP. Tumor-derived lactate and myeloid-derived suppressor cells: linking metabolism to cancer immunology. OncoImmunology 2013; 2(11): e26383

    Article  PubMed  PubMed Central  Google Scholar 

  83. Xie D, Zhu S, Bai L. Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling. Sci China Life Sci 2016; 59(12): 1290–1296

    Article  CAS  PubMed  Google Scholar 

  84. Harmon C, Robinson MW, Hand F, Almuaili D, Mentor K, Houlihan DD, Hoti E, Lynch L, Geoghegan J, O’Farrelly C. Lactate-mediated acidification of tumor microenvironment induces apoptosis of liver-resident NK Cells in colorectal liver metastasis. Cancer Immunol Res 2019; 7(2): 335–346

    Article  CAS  PubMed  Google Scholar 

  85. Goetze K, Walenta S, Ksiazkiewicz M, Kunz-Schughart LA, Mueller-Klieser W. Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release. Int J Oncol 2011; 39: 453–463

    CAS  PubMed  Google Scholar 

  86. Wei L, Zhou Y, Yao J, Qiao C, Ni T, Guo R, Guo Q, Lu N. Lactate promotes PGE2 synthesis and gluconeogenesis in monocytes to benefit the growth of inflammation-associated colorectal tumor. Oncotarget 2015; 6(18): 16198–16214

    Article  PubMed  PubMed Central  Google Scholar 

  87. Boutilier AJ, Elsawa SF. Macrophage polarization states in the tumor microenvironment. Int J Mol Sci 2021; 22(13): 6995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, Liu W, Kim S, Lee S, Perez-Neut M, Ding J, Czyz D, Hu R, Ye Z, He M, Zheng YG, Shuman HA, Dai L, Ren B, Roeder RG, Becker L, Zhao Y. Metabolic regulation of gene expression by histone lactylation. Nature 2019; 574(7779): 575–580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature 2013; 496(7446): 445–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chen AN, Luo Y, Yang YH, Fu JT, Geng XM, Shi JP, Yang J. Lactylation, a novel metabolic reprogramming code: current status and prospects. Front Immunol 2021; 12: 688910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014; 513(7519): 559–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Certo M, Tsai CH, Pucino V, Ho PC, Mauro C. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat Rev Immunol 2021; 21(3): 151–161

    Article  CAS  PubMed  Google Scholar 

  93. Liu N, Luo J, Kuang D, Xu S, Duan Y, Xia Y, Wei Z, Xie X, Yin B, Chen F, Luo S, Liu H, Wang J, Jiang K, Gong F, Tang ZH, Cheng X, Li H, Li Z, Laurence A, Wang G, Yang XP. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α-mediated tumor progression. J Clin Invest 2019; 129(2): 631–646

    Article  PubMed  PubMed Central  Google Scholar 

  94. Zhang A, Xu Y, Xu H, Ren J, Meng T, Ni Y, Zhu Q, Zhang WB, Pan YB, Jin J, Bi Y, Wu ZB, Lin S, Lou M. Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17. Theranostics 2021; 11(8): 3839–3852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Peng X, He Y, Huang J, Tao Y, Liu S. Metabolism of dendritic cells in tumor microenvironment: for immunotherapy. Front Immunol 2021; 12: 613492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Manoharan I, Prasad PD, Thangaraju M, Manicassamy S. Lactate-dependent regulation of immune responses by dendritic cells and macrophages. Front Immunol 2021; 12: 691134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Gottfried E, Kunz-Schughart LA, Ebner S, Mueller-Klieser W, Hoves S, Andreesen R, Mackensen A, Kreutz M. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 2006; 107(5): 2013–2021

    Article  CAS  PubMed  Google Scholar 

  98. Nasi A, Fekete T, Krishnamurthy A, Snowden S, Rajnavölgyi E, Catrina AI, Wheelock CE, Vivar N, Rethi B. Dendritic cell reprogramming by endogenously produced lactic acid. J Immunol 2013; 191(6): 3090–3099

    Article  CAS  PubMed  Google Scholar 

  99. Awasthi D, Nagarkoti S, Sadaf S, Chandra T, Kumar S, Dikshit M. Glycolysis dependent lactate formation in neutrophils: a metabolic link between NOX-dependent and independent NETosis. Biochim Biophys Acta Mol Basis Dis 2019; 1865(12): 165542

    Article  CAS  PubMed  Google Scholar 

  100. Ye L, Jiang Y, Zhang M. Crosstalk between glucose metabolism, lactate production and immune response modulation. Cytokine Growth Factor Rev 2022; 68: 81–92

    Article  CAS  PubMed  Google Scholar 

  101. Deng H, Kan A, Lyu N, He M, Huang X, Qiao S, Li S, Lu W, Xie Q, Chen H, Lai J, Chen Q, Jiang X, Liu S, Zhang Z, Zhao M. Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma. J Immunother Cancer 2021; 9(6): e002305

    Article  PubMed  PubMed Central  Google Scholar 

  102. Thompson LL, Guppy BJ, Sawchuk L, Davie JR, McManus KJ. Regulation of chromatin structure via histone post-translational modification and the link to carcinogenesis. Cancer Metastasis Rev 2013; 32(3–4): 363–376

    Article  CAS  PubMed  Google Scholar 

  103. Riquelme E, Zhang Y, Zhang L, Montiel M, Zoltan M, Dong W, Quesada P, Sahin I, Chandra V, San Lucas A, Scheet P, Xu H, Hanash SM, Feng L, Burks JK, Do KA, Peterson CB, Nejman D, Tzeng CD, Kim MP, Sears CL, Ajami N, Petrosino J, Wood LD, Maitra A, Straussman R, Katz M, White JR, Jenq R, Wargo J, McAllister F. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell 2019; 178(4): 795–806.e12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wu J, Li Q, Fu X. Fusobacterium nucleatum contributes to the carcinogenesis of colorectal cancer by inducing inflammation and suppressing host immunity. Transl Oncol 2019; 12(6): 846–851

    Article  PubMed  PubMed Central  Google Scholar 

  105. Gong H, Zhong H, Cheng L, Li LP, Zhang DK. Post-translational protein lactylation modification in health and diseases: a doubleedged sword. J Transl Med 2024; 22(1): 41

    Article  PubMed  PubMed Central  Google Scholar 

  106. Dong Q, Yang X, Wang L, Zhang Q, Zhao N, Nai S, Du X, Chen L. Lactylation of Hdac1 regulated by Ldh prevents the pluripotent-to-2C state conversion. Stem Cell Res Ther 2024; 15(1): 415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wu H, Liang W, Han M, Zhen Y, Chen L, Li H, An Y. Mechanisms regulating wound healing: functional changes in biology mediated by lactate and histone lactylation. J Cell Physiol 2023; 238(10): 2243–2252

    Article  CAS  PubMed  Google Scholar 

  108. Irizarry-Caro RA, McDaniel MM, Overcast GR, Jain VG, Troutman TD, Pasare C. TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation. Proc Natl Acad Sci USA 2020; 117(48): 30628–30638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Susser LI, Nguyen MA, Geoffrion M, Emerton C, Ouimet M, Khacho M, Rayner KJ. Mitochondrial fragmentation promotes inflammation resolution responses in macrophages via histone lactylation. Mol Cell Biol 2023; 43(10): 531–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wang J, Yang P, Yu T, Gao M, Liu D, Zhang J, Lu C, Chen X, Zhang X, Liu Y. Lactylation of PKM2 suppresses inflammatory metabolic adaptation in pro-inflammatory macrophages. Int J Biol Sci 2022; 18(16): 6210–6225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wang N, Wang W, Wang X, Mang G, Chen J, Yan X, Tong Z, Yang Q, Wang M, Chen L, Sun P, Yang Y, Cui J, Yang M, Zhang Y, Wang D, Wu J, Zhang M, Yu B. Histone lactylation boosts reparative gene activation post-myocardial infarction. Circ Res 2022; 131(11): 893–908

    Article  CAS  PubMed  Google Scholar 

  112. Zhang Y, Jiang H, Dong M, Min J, He X, Tan Y, Liu F, Chen M, Chen X, Yin Q, Zheng L, Shao Y, Li X, Chen H. Macrophage MCT4 inhibition activates reparative genes and protects from atherosclerosis by histone H3 lysine 18 lactylation. Cell Rep 2024; 43(5): 114180

    Article  CAS  PubMed  Google Scholar 

  113. Li J, Chen X, Song S, Jiang W, Geng T, Wang T, Xu Y, Zhu Y, Lu J, Xia Y, Wang R. Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD. Cell Rep 2025; 44(3): 115465

    Article  CAS  PubMed  Google Scholar 

  114. Landolt L, Spagnoli GC, Hertig A, Brocheriou I, Marti HP. Fibrosis and cancer: shared features and mechanisms suggest common targeted therapeutic approaches. Nephrol Dial Transplant 2022; 37(6): 1024–1032

    Article  CAS  PubMed  Google Scholar 

  115. Sun Z, Ji Z, He W, Duan R, Qu J, Yu G. Lactate accumulation induced by Akt2–PDK1 signaling promotes pulmonary fibrosis. FASEB J 2024; 38(2): e23426

    Article  CAS  PubMed  Google Scholar 

  116. Cui H, Xie N, Banerjee S, Ge J, Jiang D, Dey T, Matthews QL, Liu RM, Liu G. Lung myofibroblasts promote macrophage profibrotic activity through lactate-induced histone lactylation. Am J Respir Cell Mol Biol 2021; 64(1): 115–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Li J, Zeng G, Zhang Z, Wang Y, Shao M, Li C, Lu Z, Zhao Y, Zhang F, Ding W. Urban airborne PM2.5 induces pulmonary fibrosis through triggering glycolysis and subsequent modification of histone lactylation in macrophages. Ecotoxicol Environ Saf 2024; 273: 116162

    Article  CAS  PubMed  Google Scholar 

  118. Wang P, Xie D, Xiao T, Cheng C, Wang D, Sun J, Wu M, Yang Y, Zhang A, Liu Q. H3K18 lactylation promotes the progression of arsenite-related idiopathic pulmonary fibrosis via YTHDF1/m6A/NREP. J Hazard Mater 2024; 461: 132582

    Article  CAS  PubMed  Google Scholar 

  119. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88(1): 125–172

    Article  CAS  PubMed  Google Scholar 

  120. Rho H, Terry AR, Chronis C, Hay N. Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis. Cell Metab 2023; 35(8): 1406–1423.e8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhou Y, Yan J, Huang H, Liu L, Ren L, Hu J, Jiang X, Zheng Y, Xu L, Zhong F, Li X. The m6A reader IGF2BP2 regulates glycolytic metabolism and mediates histone lactylation to enhance hepatic stellate cell activation and liver fibrosis. Cell Death Dis 2024; 15(3): 189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Yu J, Chai P, Xie M, Ge S, Ruan J, Fan X, Jia R. Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma. Genome Biol 2021; 22(1): 85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Gu X, Zhuang A, Yu J, Yang L, Ge S, Ruan J, Jia R, Fan X, Chai P. Histone lactylation-boosted ALKBH3 potentiates tumor progression and diminished promyelocytic leukemia protein nuclear condensates by m1A demethylation of SP100A. Nucleic Acids Res 2024; 52(5): 2273–2289

    Article  CAS  PubMed  Google Scholar 

  124. Ma Z, Yang J, Jia W, Li L, Li Y, Hu J, Luo W, Li R, Ye D, Lan P. Histone lactylation-driven B7-H3 expression promotes tumor immune evasion. Theranostics 2025; 15(6): 2338–2359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhang C, Zhou L, Zhang M, Du Y, Li C, Ren H, Zheng L. H3K18 lactylation potentiates immune escape of non-small cell lung cancer. Cancer Res 2024; 84(21): 3589–3601

    Article  CAS  PubMed  Google Scholar 

  126. Pandkar MR, Sinha S, Samaiya A, Shukla S. Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression. Transl Oncol 2023; 37: 101758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wei S, Zhang J, Zhao R, Shi R, An L, Yu Z, Zhang Q, Zhang J, Yao Y, Li H, Wang H. Histone lactylation promotes malignant progression by facilitating USP39 expression to target PI3K/AKT/HIF-1α signal pathway in endometrial carcinoma. Cell Death Discov 2024; 10(1): 121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Huang ZW, Zhang XN, Zhang L, Liu LL, Zhang JW, Sun YX, Xu JQ, Liu Q, Long ZJ. STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia. Signal Transduct Target Ther 2023; 8(1): 391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Li L, Li Z, Meng X, Wang X, Song D, Liu Y, Xu T, Qin J, Sun N, Tian K, Zhong J, Yu D, Song Y, Hou T, Jiang C, Chen Q, Cai J. Histone lactylation-derived LINC01127 promotes the self-renewal of glioblastoma stem cells via the cis-regulating the MAP4K4 to activate JNK pathway. Cancer Lett 2023; 579: 216467

    Article  CAS  PubMed  Google Scholar 

  130. Yue Q, Wang Z, Shen Y, Lan Y, Zhong X, Luo X, Yang T, Zhang M, Zuo B, Zeng T, Lu J, Wang Y, Liu B, Guo H. Histone H3K9 lactylation confers temozolomide resistance in glioblastoma via LUC7L2-mediated MLH1 intron retention. Adv Sci (Weinh) 2024; 11(19): 2309290

    Article  CAS  PubMed  Google Scholar 

  131. Zhu R, Ye X, Lu X, Xiao L, Yuan M, Zhao H, Guo D, Meng Y, Han H, Luo S, Wu Q, Jiang X, Xu J, Tang Z, Tao YJ, Lu Z. ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion. Cell Metab 2025; 37(2): 361–376.e7

    Article  CAS  PubMed  Google Scholar 

  132. De Leo A, Ugolini A, Yu X, Scirocchi F, Scocozza D, Peixoto B, Pace A, D’Angelo L, Liu JKC, Etame AB, Rughetti A, Nuti M, Santoro A, Vogelbaum MA, Conejo-Garcia JR, Rodriguez PC, Veglia F. Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma. Immunity 2024; 57(5): 1105–1123.e8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Liu R, Ren X, Park YE, Feng H, Sheng X, Song X, AminiTabrizi R, Shah H, Li L, Zhang Y, Abdullah KG, Dubois-Coyne S, Lin H, Cole PA, DeBerardinis RJ, McBrayer SK, Huang H, Zhao Y. Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis. Cell Metab 2025; 37(2): 377–394.e9

    Article  CAS  PubMed  Google Scholar 

  134. Yang J, Luo L, Zhao C, Li X, Wang Z, Zeng Z, Yang X, Zheng X, Jie H, Kang L, Li S, Liu S, Zhou C, Liu H. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhao Y, Jiang J, Zhou P, Deng K, Liu Z, Yang M, Yang X, Li J, Li R, Xia J. H3K18 lactylation-mediated VCAM1 expression promotes gastric cancer progression and metastasis via AKT-mTOR-CXCL1 axis. Biochem Pharmacol 2024; 222: 116120

    Article  CAS  PubMed  Google Scholar 

  136. Li F, Si W, Xia L, Yin D, Wei T, Tao M, Cui X, Yang J, Hong T, Wei R. Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma. Mol Cancer 2024; 23(1): 90

    Article  PubMed  PubMed Central  Google Scholar 

  137. Wang J, Liu Z, Xu Y, Wang Y, Wang F, Zhang Q, Ni C, Zhen Y, Xu R, Liu Q, Fang W, Huang P, Liu X. Enterobacterial LPS-inducible LINC00152 is regulated by histone lactylation and promotes cancer cells invasion and migration. Front Cell Infect Microbiol 2022; 12: 913815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Zhou J, Xu W, Wu Y, Wang M, Zhang N, Wang L, Feng Y, Zhang T, Wang L, Mao A. GPR37 promotes colorectal cancer liver metastases by enhancing the glycolysis and histone lactylation via Hippo pathway. Oncogene 2023; 42(45): 3319–3330

    Article  CAS  PubMed  Google Scholar 

  139. Xiong J, He J, Zhu J, Pan J, Liao W, Ye H, Wang H, Song Y, Du Y, Cui B, Xue M, Zheng W, Kong X, Jiang K, Ding K, Lai L, Wang Q. Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol Cell 2022; 82(9): 1660–1677.e10

    Article  CAS  PubMed  Google Scholar 

  140. Li XM, Yang Y, Jiang FQ, Hu G, Wan S, Yan WY, He XS, Xiao F, Yang XM, Guo X, Lu JH, Yang XQ, Chen JJ, Ye WL, Liu Y, He K, Duan HX, Zhou YJ, Gan WJ, Liu F, Wu H. Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling. Cell Rep 2024; 43(2): 113688

    Article  CAS  PubMed  Google Scholar 

  141. Zhou C, Li W, Liang Z, Wu X, Cheng S, Peng J, Zeng K, Li W, Lan P, Yang X, Xiong L, Zeng Z, Zheng X, Huang L, Fan W, Liu Z, Xing Y, Kang L, Liu H. Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death. Nat Commun 2024; 15(1): 499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Li W, Zhou C, Yu L, Hou Z, Liu H, Kong L, Xu Y, He J, Lan J, Ou Q, Fang Y, Lu Z, Wu X, Pan Z, Peng J, Lin J. 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(1): 114–130

    Article  CAS  PubMed  Google Scholar 

  143. Luo Y, Yang Z, Yu Y, Zhang P. HIF1α lactylation enhances KIAA1199 transcription to promote angiogenesis and vasculogenic mimicry in prostate cancer. Int J Biol Macromol 2022; 222: 2225–2243

    Article  CAS  PubMed  Google Scholar 

  144. Chen Y, Wu J, Zhai L, Zhang T, Yin H, Gao H, Zhao F, Wang Z, Yang X, Jin M, Huang B, Ding X, Li R, Yang J, He Y, Wang Q, Wang W, Kloeber JA, Li Y, Hao B, Zhang Y, Wang J, Tan M, Li K, Wang P, Lou Z, Yuan J. Metabolic regulation of homologous recombination repair by MRE11 lactylation. Cell 2024; 187(2): 294–311.e21

    Article  CAS  PubMed  Google Scholar 

  145. Qiao Z, Li Y, Li S, Liu S, Cheng Y. Hypoxia-induced SHMT2 protein lactylation facilitates glycolysis and stemness of esophageal cancer cells. Mol Cell Biochem 2024; 479(11): 3063–3076

    Article  CAS  PubMed  Google Scholar 

  146. Sun L, Zhang Y, Yang B, Sun S, Zhang P, Luo Z, Feng T, Cui Z, Zhu T, Li Y, Qiu Z, Fan G, Huang C. Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer. Nat Commun 2023; 14(1): 6523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Jia M, Yue X, Sun W, Zhou Q, Chang C, Gong W, Feng J, Li X, Zhan R, Mo K, Zhang L, Qian Y, Sun Y, Wang A, Zou Y, Chen W, Li Y, Huang L, Yang Y, Zhao Y, Cheng X. ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation. Sci Adv 2023; 9(22): eadg4993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Miao Z, Zhao X, Liu X. Hypoxia induced β-catenin lactylation promotes the cell proliferation and stemness of colorectal cancer through the wnt signaling pathway. Exp Cell Res 2023; 422(1): 113439

    Article  CAS  PubMed  Google Scholar 

  149. Tong H, Jiang Z, Song L, Tan K, Yin X, He C, Huang J, Li X, Jing X, Yun H, Li G, Zhao Y, Kang Q, Wei Y, Li R, Long Z, Yin J, Luo Q, Liang X, Wan Y, Zheng A, Lin N, Zhang T, Xu J, Yang X, Jiang Y, Li Y, Xiang Y, Zhang Y, Feng L, Lei Z, Shi H, Ma X. Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation. Cell Metab 2024; 36(12): 2493–2510.e9

    Article  CAS  PubMed  Google Scholar 

  150. Yang L, Niu K, Wang J, Shen W, Jiang R, Liu L, Song W, Wang X, Zhang X, Zhang R, Wei D, Fan M, Jia L, Tao K. Nucleolin lactylation contributes to intrahepatic cholangiocarcinoma pathogenesis via RNA splicing regulation of MADD. J Hepatol 2024; 81(4): 651–666

    Article  CAS  PubMed  Google Scholar 

  151. Huang H, Wang S, Xia H, Zhao X, Chen K, Jin G, Zhou S, Lu Z, Chen T, Yu H, Zheng X, Huang H, Lan L. Lactate enhances NMNAT1 lactylation to sustain nuclear NAD+ salvage pathway and promote survival of pancreatic adenocarcinoma cells under glucose-deprived conditions. Cancer Lett 2024; 588: 216806

    Article  CAS  PubMed  Google Scholar 

  152. Meng Q, Sun H, Zhang Y, Yang X, Hao S, Liu B, Zhou H, Xu ZX, Wang Y. Lactylation stabilizes DCBLD1 activating the pentose phosphate pathway to promote cervical cancer progression. J Exp Clin Cancer Res 2024; 43(1): 36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Gu J, Zhou J, Chen Q, Xu X, Gao J, Li X, Shao Q, Zhou B, Zhou H, Wei S, Wang Q, Liang Y, Lu L. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells. Cell Rep 2022; 39(12): 110986

    Article  CAS  PubMed  Google Scholar 

  154. Xie Y, Hu H, Liu M, Zhou T, Cheng X, Huang W, Cao L. The role and mechanism of histone lactylation in health and diseases. Front Genet 2022; 13: 949252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Sabari BR, Zhang D, Allis CD, Zhao Y. Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol 2017; 18(2): 90–101

    Article  CAS  PubMed  Google Scholar 

  156. Ivashkiv LB. Epigenetic regulation of macrophage polarization and function. Trends Immunol 2013; 34(5): 216–223

    Article  CAS  PubMed  Google Scholar 

  157. Xie B, Zhang M, Li J, Cui J, Zhang P, Liu F, Wu Y, Deng W, Ma J, Li X, Pan B, Zhang B, Zhang H, Luo A, Xu Y, Li M, Pu Y. KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis. Proc Natl Acad Sci USA 2024; 121(8): e2314128121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Niu Z, Chen C, Wang S, Lu C, Wu Z, Wang A, Mo J, Zhang J, Han Y, Yuan Y, Zhang Y, Zang Y, He C, Bai X, Tian S, Zhai G, Wu X, Zhang K. HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription. Nat Commun 2024; 15(1): 3561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ju J, Zhang H, Lin M, Yan Z, An L, Cao Z, Geng D, Yue J, Tang Y, Tian L, Chen F, Han Y, Wang W, Zhao S, Jiao S, Zhou Z. The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer. J Clin Invest 2024; 134(10): e174587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zong Z, Xie F, Wang S, Wu X, Zhang Z, Yang B, Zhou F. Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis. Cell 2024; 187(10): 2375–2392.e33

    Article  CAS  PubMed  Google Scholar 

  161. Dong H, Zhang J, Zhang H, Han Y, Lu C, Chen C, Tan X, Wang S, Bai X, Zhai G, Tian S, Zhang T, Cheng Z, Li E, Xu L, Zhang K. YiaC and CobB regulate lysine lactylation in Escherichia coli. Nat Commun 2022; 13(1): 6628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Trujillo MN, Jennings EQ, Hoffman EA, Zhang H, Phoebe AM, Mastin GE, Kitamura N, Reisz JA, Megill E, Kantner D, Marcinkiewicz MM, Twardy SM, Lebario F, Chapman E, McCullough RL, D’Alessandro A, Snyder NW, Cusanovich DA, Galligan JJ. Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation. Mol Metab 2024; 81: 101888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Xin Q, Wang H, Li Q, Liu S, Qu K, Liu C, Zhang J. Lactylation: a passing fad or the future of posttranslational modification. Inflammation 2022; 45(4): 1419–1429

    Article  CAS  PubMed  Google Scholar 

  164. Moreno-Yruela C, Zhang D, Wei W, Bæk M, Liu W, Gao J, Danková D, Nielsen AL, Bolding JE, Yang L, Jameson ST, Wong J, Olsen CA, Zhao Y. Class I histone deacetylases (HDAC1–3) are histone lysine delactylases. Sci Adv 2022; 8(3): eabi6696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Zu H, Li C, Dai C, Pan Y, Ding C, Sun H, Zhang X, Yao X, Zang J, Mo X. SIRT2 functions as a histone delactylase and inhibits the proliferation and migration of neuroblastoma cells. Cell Discov 2022; 8(1): 54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Jin J, Bai L, Wang D, Ding W, Cao Z, Yan P, Li Y, Xi L, Wang Y, Zheng X, Wei H, Ding C, Wang Y. SIRT3-dependent delactylation of cyclin E2 prevents hepatocellular carcinoma growth. EMBO Rep 2023; 24(5): e56052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Vlachostergios PJ, Oikonomou KG, Gibilaro E, Apergis G. Elevated lactic acid is a negative prognostic factor in metastatic lung cancer. Cancer Biomark 2015; 15(6): 725–734

    Article  CAS  PubMed  Google Scholar 

  168. Xu HN, Kadlececk S, Profka H, Glickson JD, Rizi R, Li LZ. Is higher lactate an indicator of tumor metastatic risk? A pilot MRS study using hyperpolarized 13C-pyruvate. Acad Radiol 2014; 21(2): 223–231

    Article  PubMed  PubMed Central  Google Scholar 

  169. Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics. J Clin Invest 2013; 123(9): 3685–3692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Valvona CJ, Fillmore HL, Nunn PB, Pilkington GJ. The regulation and function of lactate dehydrogenase A: therapeutic potential in brain tumor. Brain Pathol 2016; 26(1): 3–17

    Article  CAS  PubMed  Google Scholar 

  171. Maiso P, Huynh D, Moschetta M, Sacco A, Aljawai Y, Mishima Y, Asara JM, Roccaro AM, Kimmelman AC, Ghobrial IM. Metabolic signature identifies novel targets for drug resistance in multiple myeloma. Cancer Res 2015; 75(10): 2071–2082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Zhou M, Zhao Y, Ding Y, Liu H, Liu Z, Fodstad O, Riker AI, Kamarajugadda S, Lu J, Owen LB, Ledoux SP, Tan M. Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A resensitizes taxol-resistant cancer cells to taxol. Mol Cancer 2010; 9(1): 33

    Article  PubMed  PubMed Central  Google Scholar 

  173. Halestrap AP, Wilson MC. The monocarboxylate transporter family–role and regulation. IUBMB Life 2012; 64(2): 109–119

    Article  CAS  PubMed  Google Scholar 

  174. Payen VL, Mina E, Van Hée VF, Porporato PE, Sonveaux P. Monocarboxylate transporters in cancer. Mol Metab 2020; 33: 48–66

    Article  CAS  PubMed  Google Scholar 

  175. Kirk P, Wilson MC, Heddle C, Brown MH, Barclay AN, Halestrap AP. CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. EMBO J 2000; 19(15): 3896–3904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Kobayashi M, Narumi K, Furugen A, Iseki K. Transport function, regulation, and biology of human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4). Pharmacol Ther 2021; 226: 107862

    Article  CAS  PubMed  Google Scholar 

  177. Pan L, Feng F, Wu J, Fan S, Han J, Wang S, Yang L, Liu W, Wang C, Xu K. Demethylzeylasteral targets lactate by inhibiting histone lactylation to suppress the tumorigenicity of liver cancer stem cells. Pharmacol Res 2022; 181: 106270

    Article  CAS  PubMed  Google Scholar 

  178. Xie B, Lin J, Chen X, Zhou X, Zhang Y, Fan M, Xiang J, He N, Hu Z, Wang F. CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer. Mol Cancer 2023; 22(1): 151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. He Y, Ji Z, Gong Y, Fan L, Xu P, Chen X, Miao J, Zhang K, Zhang W, Ma P, Zhao H, Cheng C, Wang D, Wang J, Jing N, Liu K, Zhang P, Dong B, Zhuang G, Fu Y, Xue W, Gao WQ, Zhu HH. Numb/Parkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation. Cell Rep 2023; 42(2): 112033

    Article  CAS  PubMed  Google Scholar 

  180. Yu H, Yin Y, Yi Y, Cheng Z, Kuang W, Li R, Zhong H, Cui Y, Yuan L, Gong F, Wang Z, Li H, Peng H, Zhang G. Targeting lactate dehydrogenase A (LDHA) exerts antileukemic effects on T-cell acute lymphoblastic leukemia. Cancer Commun (Lond) 2020; 40(10): 501–517

    Article  PubMed  PubMed Central  Google Scholar 

  181. Zhai X, Yang Y, Wan J, Zhu R, Wu Y. Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells. Oncol Rep 2013; 30(6): 2983–2991

    Article  CAS  PubMed  Google Scholar 

  182. Billiard J, Dennison JB, Briand J, Annan RS, Chai D, Colón M, Dodson CS, Gilbert SA, Greshock J, Jing J, Lu H, McSurdy-Freed JE, Orband-Miller LA, Mills GB, Quinn CJ, Schneck JL, Scott GF, Shaw AN, Waitt GM, Wooster RF, Duffy KJ. Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells. Cancer Metab 2013; 1(1): 19

    Article  PubMed  PubMed Central  Google Scholar 

  183. Gomez MS, Piper RC, Hunsaker LA, Royer RE, Deck LM, Makler MT, Vander Jagt DL. Substrate and cofactor specificity and selective inhibition of lactate dehydrogenase from the malarial parasite P. falciparum. Mol Biochem Parasitol 1997; 90(1): 235–246

    Article  CAS  PubMed  Google Scholar 

  184. Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA 2010; 107(5): 2037–2042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Granchi C, Calvaresi EC, Tuccinardi T, Paterni I, Macchia M, Martinelli A, Hergenrother PJ, Minutolo F. Assessing the differential action on cancer cells of LDH-A inhibitors based on the N-hydroxyindole-2-carboxylate (NHI) and malonic (Mal) scaffolds. Org Biomol Chem 2013; 11(38): 6588–6596

    Article  CAS  PubMed  Google Scholar 

  186. Boudreau A, Purkey HE, Hitz A, Robarge K, Peterson D, Labadie S, Kwong M, Hong R, Gao M, Del Nagro C, Pusapati R, Ma S, Salphati L, Pang J, Zhou A, Lai T, Li Y, Chen Z, Wei B, Yen I, Sideris S, McCleland M, Firestein R, Corson L, Vanderbilt A, Williams S, Daemen A, Belvin M, Eigenbrot C, Jackson PK, Malek S, Hatzivassiliou G, Sampath D, Evangelista M, O’Brien T. Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. Nat Chem Biol 2016; 12(10): 779–786

    Article  CAS  PubMed  Google Scholar 

  187. Nadal-Bufi F, Mason JM, Chan LY, Craik DJ, Kaas Q, Troeira Henriques S. Designed β-hairpins inhibit LDH5 oligomerization and enzymatic activity. J Med Chem 2021; 64(7): 3767–3779

    Article  CAS  PubMed  Google Scholar 

  188. Friberg A, Rehwinkel H, Nguyen D, Pütter V, Quanz M, Weiske J, Eberspächer U, Heisler I, Langer G. Structural evidence for isoform-selective allosteric inhibition of lactate dehydrogenase A. ACS Omega 2020; 5(22): 13034–13041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Kim EY, Chung TW, Han CW, Park SY, Park KH, Jang SB, Ha KT. A novel lactate dehydrogenase inhibitor, 1-(phenylseleno)-4-(trifluoromethyl) benzene, suppresses tumor growth through apoptotic cell death. Sci Rep 2019; 9(1): 3969

    Article  PubMed  PubMed Central  Google Scholar 

  190. Cui W, Lv W, Qu Y, Ma R, Wang YW, Xu YJ, Wu D, Chen X. Discovery of 2-((3-cyanopyridin-2-yl)thio)acetamides as human lactate dehydrogenase A inhibitors to reduce the growth of MG-63 osteosarcoma cells: Virtual screening and biological validation. Bioorg Med Chem Lett 2016; 26(16): 3984–3987

    Article  CAS  PubMed  Google Scholar 

  191. Fiume L, Vettraino M, Carnicelli D, Arfilli V, Di Stefano G, Brigotti M. Galloflavin prevents the binding of lactate dehydrogenase A to single stranded DNA and inhibits RNA synthesis in cultured cells. Biochem Biophys Res Commun 2013; 430(2): 466–469

    Article  CAS  PubMed  Google Scholar 

  192. Manerba M, Vettraino M, Fiume L, Di Stefano G, Sartini A, Giacomini E, Buonfiglio R, Roberti M, Recanatini M. Galloflavin (CAS 568-80-9): a novel inhibitor of lactate dehydrogenase. ChemMedChem 2012; 7(2): 311–317

    Article  CAS  PubMed  Google Scholar 

  193. Li KK, Pang JC, Ching AK, Wong CK, Kong X, Wang Y, Zhou L, Chen Z, Ng HK. miR-124 is frequently down-regulated in medulloblastoma and is a negative regulator of SLC16A1. Hum Pathol 2009; 40(9): 1234–1243

    Article  CAS  PubMed  Google Scholar 

  194. Romero-Cordoba SL, Rodriguez-Cuevas S, Bautista-Pina V, Maffuz-Aziz A, D’Ippolito E, Cosentino G, Baroni S, Iorio MV, Hidalgo-Miranda A. Loss of function of miR-342-3p results in MCT1 over-expression and contributes to oncogenic metabolic reprogramming in triple negative breast cancer. Sci Rep 2018; 8(1): 12252

    Article  PubMed  PubMed Central  Google Scholar 

  195. Liang D, Zhang Y, Han J, Wang W, Liu Y, Li J, Jiang X. Embryonic stem cell-derived pancreatic endoderm transplant with MCT1-suppressing miR-495 attenuates type II diabetes in mice. Endocr J 2015; 62(10): 907–920

    Article  CAS  PubMed  Google Scholar 

  196. Guan X, Rodriguez-Cruz V, Morris ME. Cellular uptake of MCT1 inhibitors AR-C155858 and AZD3965 and their effects on MCT-mediated transport of L-lactate in murine 4T1 breast tumor cancer cells. AAPS J 2019; 21(2): 13

    Article  PubMed  Google Scholar 

  197. Halford S, Veal GJ, Wedge SR, Payne GS, Bacon CM, Sloan P, Dragoni I, Heinzmann K, Potter S, Salisbury BM, Chénard-Poirier M, Greystoke A, Howell EC, Innes WA, Morris K, Plummer C, Rata M, Petrides G, Keun HC, Banerji U, Plummer R. A phase I dose-escalation study of AZD3965, an oral monocarboxylate transporter 1 inhibitor, in patients with advanced cancer. Clin Cancer Res 2023; 29(8): 1429–1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Ekberg H, Qi Z, Pahlman C, Veress B, Bundick RV, Craggs RI, Holness E, Edwards S, Murray CM, Ferguson D, Kerry PJ, Wilson E, Donald DK. The specific monocarboxylate transporter-1 (MCT-1) inhibitor, AR-C117977, induces donor-specific suppression, reducing acute and chronic allograft rejection in the rat. Transplantation 2007; 84(9): 1191–1199

    Article  CAS  PubMed  Google Scholar 

  199. Quanz M, Bender E, Kopitz C, Grünewald S, Schlicker A, Schwede W, Eheim A, Toschi L, Neuhaus R, Richter C, Toedling J, Merz C, Lesche R, Kamburov A, Siebeneicher H, Bauser M, Hägebarth A. Preclinical efficacy of the novel monocarboxylate transporter 1 inhibitor BAY-8002 and associated markers of resistance. Mol Cancer Ther 2018; 17(11): 2285–2296

    Article  CAS  PubMed  Google Scholar 

  200. Draoui N, Schicke O, Seront E, Bouzin C, Sonveaux P, Riant O, Feron O. Antitumor activity of 7-aminocarboxycoumarin derivatives, a new class of potent inhibitors of lactate influx but not efflux. Mol Cancer Ther 2014; 13(6): 1410–1418

    Article  CAS  PubMed  Google Scholar 

  201. Corbet C, Bastien E, Draoui N, Doix B, Mignion L, Jordan BF, Marchand A, Vanherck JC, Chaltin P, Schakman O, Becker HM, Riant O, Feron O. Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects. Nat Commun 2018; 9(1): 1208

    Article  PubMed  PubMed Central  Google Scholar 

  202. Vander Linden C, Corbet C, Bastien E, Martherus R, Guilbaud C, Petit L, Wauthier L, Loriot A, De Smet C, Feron O. Therapy-induced DNA methylation inactivates MCT1 and renders tumor cells vulnerable to MCT4 inhibition. Cell Rep 2021; 35(9): 109202

    Article  CAS  PubMed  Google Scholar 

  203. Sonveaux P, Végran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 2008; 118: 3930–3942

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Yang C, Wang M, Chang M, Yuan M, Zhang W, Tan J, Ding B, Ma P, Lin J. Heterostructural nanoadjuvant CuSe/CoSe(2) for potentiating ferroptosis and photoimmunotherapy through intratumoral blocked lactate efflux. J Am Chem Soc 2023; 145(13): 7205–7217

    Article  CAS  PubMed  Google Scholar 

  205. Cluntun AA, Badolia R, Lettlova S, Parnell KM, Shankar TS, Diakos NA, Olson KA, Taleb I, Tatum SM, Berg JA, Cunningham CN, Van Ry T, Bott AJ, Krokidi AT, Fogarty S, Skedros S, Swiatek WI, Yu X, Luo B, Merx S, Navankasattusas S, Cox JE, Ducker GS, Holland WL, McKellar SH, Rutter J, Drakos SG. The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. Cell Metab 2021; 33(3): 629–648.e10

    Article  CAS  PubMed  Google Scholar 

  206. Voss DM, Spina R, Carter DL, Lim KS, Jeffery CJ, Bar EE. Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression. Sci Rep 2017; 7(1): 4292

    Article  PubMed  PubMed Central  Google Scholar 

  207. Choi SH, Kim MY, Yoon YS, Koh DI, Kim MK, Cho SY, Kim KS, Hur MW. Hypoxia-induced RelA/p65 derepresses SLC16A3 (MCT4) by downregulating ZBTB7A. Biochim Biophys Acta Gene Regul Mech 2019; 1862(8): 771–785

    Article  CAS  PubMed  Google Scholar 

  208. Xu W, Zhang Z, Zou K, Cheng Y, Yang M, Chen H, Wang H, Zhao J, Chen P, He L, Chen X, Geng L, Gong S. MiR-1 suppresses tumor cell proliferation in colorectal cancer by inhibition of Smad3-mediated tumor glycolysis. Cell Death Dis 2017; 8(5): e2761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Zhao Y, Li W, Li M, Hu Y, Zhang H, Song G, Yang L, Cai K, Luo Z. Targeted inhibition of MCT4 disrupts intracellular pH homeostasis and confers self-regulated apoptosis on hepatocellular carcinoma. Exp Cell Res 2019; 384(1): 111591

    Article  CAS  PubMed  Google Scholar 

  210. Kobayashi M, Otsuka Y, Itagaki S, Hirano T, Iseki K. Inhibitory effects of statins on human monocarboxylate transporter 4. Int J Pharm 2006; 317(1): 19–25

    Article  CAS  PubMed  Google Scholar 

  211. Jonnalagadda S, Jonnalagadda SK, Ronayne CT, Nelson GL, Solano LN, Rumbley J, Holy J, Mereddy VR, Drewes LR. Novel N, N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors. Oncotarget 2019; 10(24): 2355–2368

    Article  PubMed  PubMed Central  Google Scholar 

  212. Saulle E, Spinello I, Quaranta MT, Pasquini L, Pelosi E, Iorio E, Castelli G, Chirico M, Pisanu ME, Ottone T, Voso MT, Testa U, Labbaye C. Targeting lactate metabolism by inhibiting MCT1 or MCT4 impairs leukemic cell proliferation, induces two different related death-pathways and increases chemotherapeutic sensitivity of acute myeloid leukemia cells. Front Oncol 2021; 10: 621458

    Article  PubMed  PubMed Central  Google Scholar 

  213. Khammanivong A, Saha J, Spartz AK, Sorenson BS, Bush AG, Korpela DM, Gopalakrishnan R, Jonnalagadda S, Mereddy VR, O’Brien TD, Drewes LR, Dickerson EB. A novel MCT1 and MCT4 dual inhibitor reduces mitochondrial metabolism and inhibits tumour growth of feline oral squamous cell carcinoma. Vet Comp Oncol 2020; 18(3): 324–341

    Article  CAS  PubMed  Google Scholar 

  214. Renner K, Bruss C, Schnell A, Koehl G, Becker HM, Fante M, Menevse AN, Kauer N, Blazquez R, Hacker L, Decking SM, Bohn T, Faerber S, Evert K, Aigle L, Amslinger S, Landa M, Krijgsman O, Rozeman EA, Brummer C, Siska PJ, Singer K, Pektor S, Miederer M, Peter K, Gottfried E, Herr W, Marchiq I, Pouyssegur J, Roush WR, Ong S, Warren S, Pukrop T, Beckhove P, Lang SA, Bopp T, Blank CU, Cleveland JL, Oefner PJ, Dettmer K, Selby M, Kreutz M. Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy. Cell Rep 2019; 29(1): 135–150.e9

    Article  CAS  PubMed  Google Scholar 

  215. Nath K, Guo L, Nancolas B, Nelson DS, Shestov AA, Lee SC, Roman J, Zhou R, Leeper DB, Halestrap AP, Blair IA, Glickson JD. Mechanism of antineoplastic activity of lonidamine. Biochim Biophys Acta 2016; 1866: 151–162

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Wilson MC, Meredith D, Fox JE, Manoharan C, Davies AJ, Halestrap AP. Basigin (CD147) is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4: the ancillary protein for the insensitive MCT2 is EMBIGIN (gp70). J Biol Chem 2005; 280(29): 27213–27221

    Article  CAS  PubMed  Google Scholar 

  217. Fu ZG, Wang L, Cui HY, Peng JL, Wang SJ, Geng JJ, Liu JD, Feng F, Song F, Li L, Zhu P, Jiang JL, Chen ZN. A novel smallmolecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells. Oncotarget 2016; 7(8): 9429–9447

    Article  PubMed  PubMed Central  Google Scholar 

  218. Baba M, Inoue M, Itoh K, Nishizawa Y. Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism. Biochem Biophys Res Commun 2008; 374(1): 111–116

    Article  CAS  PubMed  Google Scholar 

  219. Gao F, Tang Y, Liu WL, Zou MZ, Huang C, Liu CJ, Zhang XZ. Intra/extracellular lactic acid exhaustion for synergistic metabolic therapy and immunotherapy of tumors. Adv Mater 2019; 31(51): e1904639

    Article  PubMed  Google Scholar 

  220. Wang H, Wang B, Jiang J, Wu Y, Song A, Wang X, Yao C, Dai H, Xu J, Zhang Y, Ma Q, Xu F, Li R, Wang C. SnSe Nanosheets Mimic Lactate Dehydrogenase to Reverse Tumor Acid Microenvironment Metabolism for Enhancement of Tumor Therapy. Molecules 2022; 27(23): 8552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Xu H, Li L, Wang S, Wang Z, Qu L, Wang C, Xu K. Royal jelly acid suppresses hepatocellular carcinoma tumorigenicity by inhibiting H3 histone lactylation at H3K9la and H3K14la sites. Phytomedicine 2023; 118: 154940

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 8227061256 and 871386269 to Peixiang Lan; No. 82171760 to Song Chen), Startup Funding from Tongji Hospital (to Peixiang Lan).

Author information

Authors and Affiliations

  1. Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Liu Song, Song Chen & Peixiang Lan

  2. Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China

    Liu Song, Song Chen & Peixiang Lan

  3. Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Lingjuan Sun

Authors
  1. Liu Song
    View author publications

    Search author on:PubMed Google Scholar

  2. Lingjuan Sun
    View author publications

    Search author on:PubMed Google Scholar

  3. Song Chen
    View author publications

    Search author on:PubMed Google Scholar

  4. Peixiang Lan
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Song Chen or Peixiang Lan.

Ethics declarations

Conflicts of interest Liu Song, Lingjuan Sun, Song Chen, and Peixiang Lan declare no conflicts of interest.

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, L., Sun, L., Chen, S. et al. Lactate and lactylation in tumor immunity. Front. Med. (2025). https://doi.org/10.1007/s11684-025-1148-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11684-025-1148-0

Keywords