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Abstract

In recent years, immunotherapy has demonstrated significant clinical effectiveness. However, challenges such as low response rates, severe treatment-related side effects, and acquired immune tolerance persist in tumor immunotherapy. Metabolic dysregulation is acknowledged as a principal factor in tumor growth, with aerobic glycolysis, or the Warburg effect, being a defining characteristic of numerous cancers. The enhanced uptake of glucose and glycolysis provides the necessary intermediates for anabolic reactions, which are essential for the proliferation of cancer cells, while simultaneously supplying sufficient energy. However, the concomitant increase in lactate production contributes to immunosuppression within the tumor microenvironment. Tumor cells exploit lactate anabolism, lactate shuttling, and lysine lactylation modifications, which significantly diminish the efficacy of immunotherapy. The treatment targeting lactate anabolism or lactate transport proteins may prove an effective strategy for enhancing the effectiveness of cancer immunotherapy. This review provides a comprehensive overview of the role of lactate in anti-tumor immunotherapy, with the objective of deepening the understanding of the importance of lactate monitoring in cancer treatment. By elucidating these mechanisms, we aim to suggest innovative avenues for clinical cancer management, potentially improving therapeutic outcomes and overcoming the existing limitations of immunotherapy.

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2025-07-17
2025-09-13
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References

  1. Bray F. Laversanne M. Sung H. Ferlay J. Siegel R.L. Soerjomataram I. Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024 74 3 229 263 10.3322/caac.21834 38572751
    [Google Scholar]
  2. Zhang Y. Zhang Z. The history and advances in cancer immunotherapy: Understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell. Mol. Immunol. 2020 17 8 807 821 10.1038/s41423‑020‑0488‑6 32612154
    [Google Scholar]
  3. Wang Q. Wu X. Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment. Int. Immunopharmacol. 2017 46 210 219 10.1016/j.intimp.2017.03.015 28324831
    [Google Scholar]
  4. Newell F. Pires da Silva I. Johansson P.A. Menzies A.M. Wilmott J.S. Addala V. Carlino M.S. Rizos H. Nones K. Edwards J.J. Lakis V. Kazakoff S.H. Mukhopadhyay P. Ferguson P.M. Leonard C. Koufariotis L.T. Wood S. Blank C.U. Thompson J.F. Spillane A.J. Saw R.P.M. Shannon K.F. Pearson J.V. Mann G.J. Hayward N.K. Scolyer R.A. Waddell N. Long G.V. Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance. Cancer Cell 2022 40 1 88 102.e7 10.1016/j.ccell.2021.11.012 34951955
    [Google Scholar]
  5. Jing Y. Liu J. Ye Y. Pan L. Deng H. Wang Y. Yang Y. Diao L. Lin S.H. Mills G.B. Zhuang G. Xue X. Han L. Multi-omics prediction of immune-related adverse events during checkpoint immunotherapy. Nat. Commun. 2020 11 1 4946 10.1038/s41467‑020‑18742‑9 33009409
    [Google Scholar]
  6. Li Y. Yue L. Zhang S. Wang X. Zhu Y. Liu J. Ren H. Jiang W. Wang J. Zhang Z. Liu T. Proteomic, single-cell and bulk transcriptomic analysis of plasma and tumor tissues unveil core proteins in response to anti-PD-L1 immunotherapy in triple negative breast cancer. Comput. Biol. Med. 2024 176 108537 10.1016/j.compbiomed.2024.108537 38744008
    [Google Scholar]
  7. Chen L. Huang L. Gu Y. Cang W. Sun P. Xiang Y. Lactate-lactylation hands between metabolic reprogramming and immunosuppression. Int. J. Mol. Sci. 2022 23 19 11943 10.3390/ijms231911943 36233246
    [Google Scholar]
  8. Sun J. Feng Q. Xu Y. Liu P. Wu Y. Analysis of prognostic value of lactate metabolism-related genes in ovarian cancer based on bioinformatics. J. Ovarian Res. 2024 17 1 110 10.1186/s13048‑024‑01426‑z 38778371
    [Google Scholar]
  9. Vlachostergios P.J. Oikonomou K.G. Gibilaro E. Apergis G. Elevated lactic acid is a negative prognostic factor in metastatic lung cancer. Cancer Biomark. 2015 15 6 725 734 10.3233/CBM‑150514 26406401
    [Google Scholar]
  10. Jiao Y. Ji F. Hou L. Lv Y. Zhang J. Lactylation-related gene signature for prognostic prediction and immune infiltration analysis in breast cancer. Heliyon 2024 10 3 24777 10.1016/j.heliyon.2024.e24777 38318076
    [Google Scholar]
  11. Liberti M.V. Locasale J.W. The warburg effect: How does it benefit cancer cells? Trends Biochem. Sci. 2016 41 3 211 218 10.1016/j.tibs.2015.12.001 26778478
    [Google Scholar]
  12. Ngo D.C. Ververis K. Tortorella S.M. Karagiannis T.C. Introduction to the molecular basis of cancer metabolism and the Warburg effect. Mol. Biol. Rep. 2015 42 4 819 823 10.1007/s11033‑015‑3857‑y 25672512
    [Google Scholar]
  13. Kobayashi Y. Banno K. Kunitomi H. Takahashi T. Takeda T. Nakamura K. Tsuji K. Tominaga E. Aoki D. Warburg effect in Gynecologic cancers. J. Obstet. Gynaecol. Res. 2019 45 3 542 548 10.1111/jog.13867 30511455
    [Google Scholar]
  14. Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009 324 5930 1029 1033 10.1126/science.1160809 19460998
    [Google Scholar]
  15. Reinfeld B.I. Madden M.Z. Wolf M.M. Chytil A. Bader J.E. Patterson A.R. Sugiura A. Cohen A.S. Ali A. Do B.T. Muir A. Lewis C.A. Hongo R.A. Young K.L. Brown R.E. Todd V.M. Huffstater T. Abraham A. O’Neil R.T. Wilson M.H. Xin F. Tantawy M.N. Merryman W.D. Johnson R.W. Williams C.S. Mason E.F. Mason F.M. Beckermann K.E. Vander Heiden M.G. Manning H.C. Rathmell J.C. Rathmell W.K. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 2021 593 7858 282 288 10.1038/s41586‑021‑03442‑1 33828302
    [Google Scholar]
  16. Scalise M. Pochini L. Galluccio M. Console L. Indiveri C. Glutamine transport and mitochondrial metabolism in cancer cell growth. Front. Oncol. 2017 7 306 10.3389/fonc.2017.00306 29376023
    [Google Scholar]
  17. Szeliga M. Albrecht J. Glutamine metabolism in gliomas. Adv. Neurobiol. 2016 13 259 273 10.1007/978‑3‑319‑45096‑4_9 27885632
    [Google Scholar]
  18. Ye Y. Yu B. Wang H. Yi F. Glutamine metabolic reprogramming in hepatocellular carcinoma. Front. Mol. Biosci. 2023 10 1242059 10.3389/fmolb.2023.1242059 37635935
    [Google Scholar]
  19. Pavlides S. Whitaker-Menezes D. Castello-Cros R. Flomenberg N. Witkiewicz A.K. Frank P.G. Casimiro M.C. Wang C. Fortina P. Addya S. Pestell R.G. Martinez-Outschoorn U.E. Sotgia F. Lisanti M.P. The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 2009 8 23 3984 4001 10.4161/cc.8.23.10238 19923890
    [Google Scholar]
  20. Li M. Yang Y. Xiong L. Jiang P. Wang J. Li C. Metabolism, metabolites, and macrophages in cancer. J. Hematol. Oncol. 2023 16 1 80 10.1186/s13045‑023‑01478‑6 37491279
    [Google Scholar]
  21. Chen D. Liu P. Lu X. Li J. Qi D. Zang L. Lin J. Liu Y. Zhai S. Fu D. Weng Y. Li H. Shen B. Pan-cancer analysis implicates novel insights of lactate metabolism into immunotherapy response prediction and survival prognostication. J. Exp. Clin. Cancer Res. 2024 43 1 125 10.1186/s13046‑024‑03042‑7 38664705
    [Google Scholar]
  22. Low V. Li Z. Blenis J. Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment. Sci. Signal. 2022 15 759 eabj4220 10.1126/scisignal.abj4220 36346837
    [Google Scholar]
  23. Halestrap A.P. The SLC16 gene family – Structure, role and regulation in health and disease. Mol. Aspects Med. 2013 34 2-3 337 349 10.1016/j.mam.2012.05.003 23506875
    [Google Scholar]
  24. Peralta R.M. Xie B. Lontos K. Nieves-Rosado H. Spahr K. Joshi S. Ford B.R. Quann K. Frisch A.T. Dean V. Philbin M. Cillo A.R. Gingras S. Poholek A.C. Kane L.P. Rivadeneira D.B. Delgoffe G.M. Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism. Nat. Immunol. 2024 25 12 2297 2307 10.1038/s41590‑024‑01999‑3 39516648
    [Google Scholar]
  25. Miranda-Gonçalves V. Honavar M. Pinheiro C. Martinho O. Pires M.M. Pinheiro C. Cordeiro M. Bebiano G. Costa P. Palmeirim I. Reis R.M. Baltazar F. Monocarboxylate transporters (MCTs) in gliomas: Expression and exploitation as therapeutic targets. Neuro-oncol. 2013 15 2 172 188 10.1093/neuonc/nos298 23258846
    [Google Scholar]
  26. Khammanivong A. Saha J. Spartz A.K. Sorenson B.S. Bush A.G. Korpela D.M. Gopalakrishnan R. Jonnalagadda S. Mereddy V.R. O’Brien T.D. Drewes L.R. Dickerson E.B. 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 10.1111/vco.12551 31661586
    [Google Scholar]
  27. Brown T.P. 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 10.1016/j.pharmthera.2019.107451 31836453
    [Google Scholar]
  28. Chen P. Zuo H. Xiong H. Kolar M.J. Chu Q. Saghatelian A. Siegwart D.J. 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 10.1073/pnas.1614035114 28049847
    [Google Scholar]
  29. li, X.; Chen, Y.; Wang, T.; Liu, Z.; Yin, G.; Wang, Z.; Sui, C.; Zhu, L.; Chen, W. GPR81-mediated reprogramming of glucose metabolism contributes to the immune landscape in breast cancer. Discov. Oncol. 2023 14 1 140 10.1007/s12672‑023‑00709‑z 37500811
    [Google Scholar]
  30. Yang K. Xu J. Fan M. Tu F. Wang X. Ha T. Williams D.L. Li C. Lactate suppresses macrophage pro-inflammatory response to lps stimulation by inhibition of YAP and NF-κB Activation via GPR81-mediated signaling. Front. Immunol. 2020 11 587913 10.3389/fimmu.2020.587913 33123172
    [Google Scholar]
  31. Chi H. Pepper M. Thomas P.G. Principles and therapeutic applications of adaptive immunity. Cell 2024 187 9 2052 2078 10.1016/j.cell.2024.03.037 38670065
    [Google Scholar]
  32. Downs-Canner S.M. Meier J. Vincent B.G. Serody J.S. B cell function in the tumor microenvironment. Annu. Rev. Immunol. 2022 40 1 169 193 10.1146/annurev‑immunol‑101220‑015603 35044794
    [Google Scholar]
  33. Farhood B. Najafi M. Mortezaee K. CD8 + cytotoxic T lymphocytes in cancer immunotherapy: A review. J. Cell. Physiol. 2019 234 6 8509 8521 10.1002/jcp.27782 30520029
    [Google Scholar]
  34. 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 S.W. Kreutz M. Inhibitory effect of tumor cell–derived lactic acid on human T cells. Blood 2007 109 9 3812 3819 10.1182/blood‑2006‑07‑035972 17255361
    [Google Scholar]
  35. Martinis E. Tonon S. Colamatteo A. La Cava A. Matarese G. Pucillo C.E.M. B cell immunometabolism in health and disease. Nat. Immunol. 2025 26 3 366 377 10.1038/s41590‑025‑02102‑0 39984733
    [Google Scholar]
  36. Liu Y. Wang F. Peng D. Zhang D. Liu L. Wei J. Yuan J. Zhao L. Jiang H. Zhang T. Li Y. Zhao C. He S. Wu J. Yan Y. Zhang P. Guo C. Zhang J. Li X. Gao H. Li K. Activation and antitumor immunity of CD8 + T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid. Sci. Transl. Med. 2024 16 762 eadk7399 10.1126/scitranslmed.adk7399 39196962
    [Google Scholar]
  37. Elia I. Rowe J.H. Johnson S. Joshi S. Notarangelo G. Kurmi K. Weiss S. Freeman G.J. Sharpe A.H. Haigis M.C. 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 10.1016/j.cmet.2022.06.008 35820416
    [Google Scholar]
  38. 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 10.1007/s11427‑016‑0348‑7 27995420
    [Google Scholar]
  39. Barbieri L. Veliça P. Gameiro P.A. Cunha P.P. Foskolou I.P. Rullman E. Bargiela D. Johnson R.S. Rundqvist H. Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells. Front. Immunol. 2023 14 1101433 10.3389/fimmu.2023.1101433 36923405
    [Google Scholar]
  40. Apostolova P. Pearce E.L. Lactic acid and lactate: Revisiting the physiological roles in the tumor microenvironment. Trends Immunol. 2022 43 12 969 977 10.1016/j.it.2022.10.005 36319537
    [Google Scholar]
  41. Feng Q. Liu Z. Yu X. Huang T. Chen J. Wang J. Wilhelm J. Li S. Song J. Li W. Sun Z. Sumer B.D. Li B. Fu Y.X. Gao J. Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity. Nat. Commun. 2022 13 1 4981 10.1038/s41467‑022‑32521‑8 36068198
    [Google Scholar]
  42. Wang Z. Shang J. Qiu Y. Cheng H. Tao M. Xie E. Pei X. Li W. Zhang L. Wu A. Li G. Suppression of the METTL3-m6A-integrin β1 axis by extracellular acidification impairs T cell infiltration and antitumor activity. Cell Rep. 2024 43 2 113796 10.1016/j.celrep.2024.113796 38367240
    [Google Scholar]
  43. Klabusay M. [The role of regulatory T-cells in antitumor immune response]. Klin Onkol 2015 28 (Suppl 4), 4s23 4s27
    [Google Scholar]
  44. Brand A. Singer K. Koehl G.E. 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 P.J. Hoffmann P. Walenta S. Geissler E.K. 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 10.1016/j.cmet.2016.08.011 27641098
    [Google Scholar]
  45. Watson M.J. Vignali P.D.A. Mullett S.J. Overacre-Delgoffe A.E. Peralta R.M. Grebinoski S. Menk A.V. Rittenhouse N.L. DePeaux K. Whetstone R.D. Vignali D.A.A. Hand T.W. Poholek A.C. Morrison B.M. Rothstein J.D. Wendell S.G. Delgoffe G.M. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 2021 591 7851 645 651 10.1038/s41586‑020‑03045‑2 33589820
    [Google Scholar]
  46. Angelin A. Gil-de-Gómez L. Dahiya S. Jiao J. Guo L. Levine M.H. Wang Z. Quinn W.J. Kopinski P.K. Wang L. Akimova T. Liu Y. Bhatti T.R. Han R. Laskin B.L. Baur J.A. Blair I.A. Wallace D.C. Hancock W.W. Beier U.H. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017 25 6 1282 1293.e7 10.1016/j.cmet.2016.12.018 28416194
    [Google Scholar]
  47. Ding R. Yu X. Hu Z. Dong Y. Huang H. Zhang Y. Han Q. Ni Z.Y. 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 10.1016/j.immuni.2024.01.019 38417442
    [Google Scholar]
  48. Verma S. Budhu S. Serganova I. Dong L. Mangarin L.M. Khan J.F. Bah M.A. Assouvie A. Marouf Y. Schulze I. Zappasodi R. Wolchok J.D. Merghoub T. Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models. J. Clin. Invest. 2024 134 17 177606 10.1172/JCI177606 39225102
    [Google Scholar]
  49. 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 10.1016/j.celrep.2022.110986 35732125
    [Google Scholar]
  50. Kumagai S. Koyama S. Itahashi K. Tanegashima T. Lin Y. 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 10.1016/j.ccell.2022.01.001 35090594
    [Google Scholar]
  51. Pradeu T. Thomma B.P.H.J. Girardin S.E. Lemaitre B. The conceptual foundations of innate immunity: Taking stock 30 years later. Immunity 2024 57 4 613 631 10.1016/j.immuni.2024.03.007 38599162
    [Google Scholar]
  52. Li H. Liu C. Li R. Zhou L. Ran Y. Yang Q. Huang H. Lu H. Song H. Yang B. Ru H. Lin S. Zhang L. AARS1 and AARS2 sense l-lactate to regulate cGAS as global lysine lactyltransferases. Nature 2024 634 8036 1229 1237 10.1038/s41586‑024‑07992‑y 39322678
    [Google Scholar]
  53. Llibre A. Kucuk S. Gope A. Certo M. Mauro C. Lactate: A key regulator of the immune response. Immunity 2025 58 3 535 554 10.1016/j.immuni.2025.02.008 40073846
    [Google Scholar]
  54. Sanmarco L.M. Rone J.M. Polonio C.M. Fernandez Lahore G. Giovannoni F. Ferrara K. Gutierrez-Vazquez C. Li N. Sokolovska A. Plasencia A. Faust Akl C. Nanda P. Heck E.S. Li Z. Lee H.G. Chao C.C. Rejano-Gordillo C.M. Fonseca-Castro P.H. Illouz T. Linnerbauer M. Kenison J.E. Barilla R.M. Farrenkopf D. Stevens N.A. Piester G. Chung E.N. Dailey L. Kuchroo V.K. Hava D. Wheeler M.A. Clish C. Nowarski R. Balsa E. Lora J.M. Quintana F.J. Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells. Nature 2023 620 7975 881 889 10.1038/s41586‑023‑06409‑6 37558878
    [Google Scholar]
  55. Zhao Q. Wang Q. Yao Q. Yang Z. Li W. Cheng X. Wen Y. Chen R. Xu J. Wang X. Qin D. Zhu S. He L. Li N. Wu Y. Yu Y. Cao X. Wang P. Nonenzymatic lysine d-lactylation induced by glyoxalase II substrate SLG dampens inflammatory immune responses. Cell Res. 2025 35 2 97 116 10.1038/s41422‑024‑01060‑w 39757301
    [Google Scholar]
  56. Vivier E. Rebuffet L. Narni-Mancinelli E. Cornen S. Igarashi R.Y. Fantin V.R. Natural killer cell therapies. Nature 2024 626 8000 727 736 10.1038/s41586‑023‑06945‑1 38383621
    [Google Scholar]
  57. Jia H. Yang H. Xiong H. Luo K.Q. NK cell exhaustion in the tumor microenvironment. Front. Immunol. 2023 14 1303605 10.3389/fimmu.2023.1303605 38022646
    [Google Scholar]
  58. Jedlička M. Feglarová T. Janstová L. Hortová-Kohoutková M. Frič J. Lactate from the tumor microenvironment - A key obstacle in NK cell-based immunotherapies. Front. Immunol. 2022 13 932055 10.3389/fimmu.2022.932055 36330529
    [Google Scholar]
  59. Hui X. Xue M. Ren Y. Chen Y. Chen X. Farooq M.A. Ji Y. Zhan W. Huang Y. Du B. Yao J. Duan Y. Jiang W. GPR132 regulates the function of NK cells through the Gαs/CSK/ZAP70/NF-κB signaling pathway as a potential immune checkpoint. Sci. Adv. 2025 11 10 eadr9395 10.1126/sciadv.adr9395 40043109
    [Google Scholar]
  60. Pötzl J. Roser D. Bankel L. Hömberg N. Geishauser A. Brenner C.D. Weigand M. Röcken M. Mocikat R. Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN‐γ and induces NK cell‐dependent lymphoma control without other immunotherapies. Int. J. Cancer 2017 140 9 2125 2133 10.1002/ijc.30646 28195314
    [Google Scholar]
  61. Tao H. Zhong X. Zeng A. Song L. Unveiling the veil of lactate in tumor-associated macrophages: A successful strategy for immunometabolic therapy. Front. Immunol. 2023 14 1208870 10.3389/fimmu.2023.1208870 37564659
    [Google Scholar]
  62. Zhou H. Xin yan Yu, W.; Liang, X.; Du, X.; Liu, Z.; Long, J.; Zhao, G.; Liu, H. Lactic acid in macrophage polarization: The significant role in inflammation and cancer. Int. Rev. Immunol. 2022 41 1 4 18 10.1080/08830185.2021.1955876 34304685
    [Google Scholar]
  63. 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 Z. Cheng X. Li H. Li Z. Laurence A. Wang G. Yang X.P. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α–mediated tumor progression. J. Clin. Invest. 2019 129 2 631 646 10.1172/JCI123027 30431439
    [Google Scholar]
  64. Meng B. Zhao N. Mlcochova P. Ferreira I.A.T.M. Ortmann B.M. Davis T. Wit N. Rehwinkel J. Cook S. Maxwell P.H. Nathan J.A. Gupta R.K. Hypoxia drives HIF2-dependent reversible macrophage cell cycle entry. Cell Rep. 2024 43 7 114471 10.1016/j.celrep.2024.114471 38996069
    [Google Scholar]
  65. Vadevoo S.M.P. Gunassekaran G.R. Lee C. Lee N. Lee J. Chae S. Park J.Y. 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 2102434118 10.1073/pnas.2102434118 34504016
    [Google Scholar]
  66. Koenderman L. Vrisekoop N. Neutrophils in cancer: From biology to therapy. Cell. Mol. Immunol. 2024 22 1 4 23 10.1038/s41423‑024‑01244‑9 39653768
    [Google Scholar]
  67. 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 002305 10.1136/jitc‑2020‑002305 34168004
    [Google Scholar]
  68. Moon C.Y. Belabed M. Park M.D. Mattiuz R. Puleston D. Merad M. Dendritic cell maturation in cancer. Nat. Rev. Cancer 2025 25 4 225 248 10.1038/s41568‑024‑00787‑3 39920276
    [Google Scholar]
  69. Plebanek M.P. Xue Y. Nguyen Y.V. DeVito N.C. Wang X. Holtzhausen A. Beasley G.M. Theivanthiran B. Hanks B.A. A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression. Sci. Immunol. 2024 9 95 eadi4191 10.1126/sciimmunol.adi4191 38728412
    [Google Scholar]
  70. Park S.Y. Pylaeva E. Bhuria V. Gambardella A.R. Schiavoni G. Mougiakakos D. Kim S.H. Jablonska J. Harnessing myeloid cells in cancer. Mol. Cancer 2025 24 1 69 10.1186/s12943‑025‑02249‑2 40050933
    [Google Scholar]
  71. He J. Chai X. Zhang Q. Wang Y. Wang Y. Yang X. Wu J. Feng B. Sun J. Rui W. Ze S. Fu Y. Zhao Y. Zhang Y. Zhang Y. Liu M. Liu C. She M. Hu X. Ma X. Yang H. Li D. Zhao S. Li G. Zhang Z. Tian Z. Ma Y. Cao L. Yi B. Li D. Nussinov R. Eng C. Chan T.A. Ruppin E. Gutkind J.S. Cheng F. Liu M. Lu W. The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer. Nat. Immunol. 2025 26 3 391 403 10.1038/s41590‑024‑02068‑5 39905201
    [Google Scholar]
  72. Li W. Tanikawa T. Kryczek I. Xia H. Li G. Wu K. Wei S. Zhao L. Vatan L. Wen B. Shu P. Sun D. Kleer C. Wicha M. Sabel M. Tao K. Wang G. Zou W. Aerobic glycolysis controls myeloid-derived suppressor cells and tumor immunity via a specific CEBPB isoform in triple-negative breast cancer. Cell Metab. 2018 28 1 87 103.e6 10.1016/j.cmet.2018.04.022 29805099
    [Google Scholar]
  73. Li J. Qiao H. Wu F. Sun S. Feng C. Li C. Yan W. Lv W. Wu H. Liu M. Chen X. Liu X. Wang W. Cai Y. Zhang Y. Zhou Z. Zhang Y. Zhang S. A novel hypoxia- and lactate metabolism-related signature to predict prognosis and immunotherapy responses for breast cancer by integrating machine learning and bioinformatic analyses. Front. Immunol. 2022 13 998140 10.3389/fimmu.2022.998140 36275774
    [Google Scholar]
  74. Jiang K. Zhu L. Huang H. Zheng L. Wang Z. Kang X. Lactate score classification of hepatocellular carcinoma helps identify patients with tumors that respond to immune checkpoint blockade therapy. Cell. Oncol. 2024 47 1 175 188 10.1007/s13402‑023‑00861‑2 37612583
    [Google Scholar]
  75. Xue Q. Peng W. Zhang S. Wei X. Ye L. Wang Z. Xiang X. Liu Y. Wang H. Zhou Q. Lactylation-driven TNFR2 expression in regulatory T cells promotes the progression of malignant pleural effusion. J. Immunother. Cancer 2024 12 12 010040 10.1136/jitc‑2024‑010040 39721754
    [Google Scholar]
  76. Wang Z. Zhang S. Li J. Yuan Y. Chen S. Zuo M. Li W. Feng W. Chen M. Liu Y. Prognostic value of lactate metabolism-related gene expression signature in adult primary gliomas and its impact on the tumor immune microenvironment. Front. Oncol. 2022 12 1008219 10.3389/fonc.2022.1008219 36203434
    [Google Scholar]
  77. Fu S. Xu J. Wang C. Zhang C. Li C. Xie W. Wang G. Zhu X. Xu Y. Wen Y. Pei J. Yang J. Tang M. Tan H. Cai S. Cai L. Pan M. Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysis. Heliyon 2024 10 23 39491 10.1016/j.heliyon.2024.e39491 39669156
    [Google Scholar]
  78. Deng Y. Zhu G. Mi X. Jing X. Prognostic implication of a novel lactate score correlating with immunotherapeutic responses in pan-cancer. Aging 2024 16 1 820 843 10.18632/aging.205423 38198170
    [Google Scholar]
  79. Chetta P. Sriram R. Zadra G. Lactate as key metabolite in prostate cancer progression: What are the clinical implications? Cancers 2023 15 13 3473 10.3390/cancers15133473 37444583
    [Google Scholar]
  80. Wang G. Wang J.J. Yin P.H. Xu K. Wang Y.Z. Shi F. Gao J. Fu X.L. New strategies for targeting glucose metabolism–mediated acidosis for colorectal cancer therapy. J. Cell. Physiol. 2019 234 1 348 368 10.1002/jcp.26917 30069931
    [Google Scholar]
  81. Hensley C.T. Faubert B. Yuan Q. Lev-Cohain N. Jin E. Kim J. Jiang L. Ko B. Skelton R. Loudat L. Wodzak M. Klimko C. McMillan E. Butt Y. Ni M. Oliver D. Torrealba J. Malloy C.R. Kernstine K. Lenkinski R.E. DeBerardinis R.J. Metabolic heterogeneity in human lung tumors. Cell 2016 164 4 681 694 10.1016/j.cell.2015.12.034 26853473
    [Google Scholar]
  82. Yoshida G.J. Metabolic reprogramming: The emerging concept and associated therapeutic strategies. J. Exp. Clin. Cancer Res. 2015 34 1 111 10.1186/s13046‑015‑0221‑y 26445347
    [Google Scholar]
  83. Nguyen N.T.B. Gevers S. Kok R.N.U. Burgering L.M. Neikes H. Akkerman N. Betjes M.A. Ludikhuize M.C. Gulersonmez C. Stigter E.C.A. Vercoulen Y. Drost J. Clevers H. Vermeulen M. van Zon J.S. Tans S.J. Burgering B.M.T. Rodríguez Colman M.J. Lactate controls cancer stemness and plasticity through epigenetic regulation. Cell Metab. 2025 37 4 903 919.e10 10.1016/j.cmet.2025.01.002 39933514
    [Google Scholar]
  84. Neves A.R. Albuquerque T. Quintela T. Costa D. Circadian rhythm and disease: Relationship, new insights, and future perspectives. J. Cell. Physiol. 2022 237 8 3239 3256 10.1002/jcp.30815 35696609
    [Google Scholar]
  85. Wang Z. Ma L. Meng Y. Fang J. Xu D. Lu Z. The interplay of the circadian clock and metabolic tumorigenesis. Trends Cell Biol. 2024 34 9 742 755 10.1016/j.tcb.2023.11.004 38061936
    [Google Scholar]
  86. Wang J. Huang Q. Hu X. Zhang S. Jiang Y. Yao G. Hu K. Xu X. Liang B. Wu Q. Ma Z. Wang Y. Wang C. Wu Z. Rong X. Liao W. Shi M. Disrupting circadian rhythm via the PER1–HK2 axis reverses trastuzumab resistance in gastric cancer. Cancer Res. 2022 82 8 1503 1517 10.1158/0008‑5472.CAN‑21‑1820 35255118
    [Google Scholar]
  87. Li Z. Wang Q. Huang X. Yang M. Zhou S. Li Z. Fang Z. Tang Y. Chen Q. Hou H. Li L. Fei F. Wang Q. Wu Y. Gong A. Lactate in the tumor microenvironment: A rising star for targeted tumor therapy. Front. Nutr. 2023 10 1113739 10.3389/fnut.2023.1113739 36875841
    [Google Scholar]
  88. Xu Y. Hao X. Ren Y. Xu Q. Liu X. Song S. Wang Y. Research progress of abnormal lactate metabolism and lactate modification in immunotherapy of hepatocellular carcinoma. Front. Oncol. 2023 12 1063423 10.3389/fonc.2022.1063423 36686771
    [Google Scholar]
  89. Peek C.B. Metabolic implications of circadian–HIF crosstalk. Trends Endocrinol. Metab. 2020 31 6 459 468 10.1016/j.tem.2020.02.008 32396846
    [Google Scholar]
  90. Wang C. Zeng Q. Gül Z.M. Wang S. Pick R. Cheng P. Bill R. Wu Y. Naulaerts S. Barnoud C. Hsueh P.C. Moller S.H. Cenerenti M. Sun M. Su Z. Jemelin S. Petrenko V. Dibner C. Hugues S. Jandus C. Li Z. Michielin O. Ho P.C. Garg A.D. Simonetta F. Pittet M.J. Scheiermann C. Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy. Cell 2024 187 11 2690 2702.e17 10.1016/j.cell.2024.04.015 38723627
    [Google Scholar]
  91. El-Tanani M. Rabbani S.A. Ali A.A. Alfaouri I.G.A. Al Nsairat H. Al-Ani I.H. Aljabali A.A. Rizzo M. Patoulias D. Khan M.A. Parvez S. El-Tanani Y. Circadian rhythms and cancer: Implications for timing in therapy. Discover. Oncology. 2024 15 1 767 10.1007/s12672‑024‑01643‑4 39692981
    [Google Scholar]
  92. Frisardi V. Canovi S. Vaccaro S. Frazzi R. The significance of microenvironmental and circulating lactate in breast cancer. Int. J. Mol. Sci. 2023 24 20 15369 10.3390/ijms242015369 37895048
    [Google Scholar]
  93. Chen S. Xu Y. Zhuo W. Zhang L. The emerging role of lactate in tumor microenvironment and its clinical relevance. Cancer Lett. 2024 590 216837 10.1016/j.canlet.2024.216837 38548215
    [Google Scholar]
  94. Erra Díaz F. Dantas E. Geffner J. Unravelling the interplay between extracellular acidosis and immune cells. Mediators Inflamm. 2018 2018 1 11 10.1155/2018/1218297 30692870
    [Google Scholar]
  95. Helmlinger G. Yuan F. Dellian M. Jain R.K. Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation. Nat. Med. 1997 3 2 177 182 10.1038/nm0297‑177 9018236
    [Google Scholar]
  96. Schornack P.A. Gillies R.J. Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors. Neoplasia 2003 5 2 135 145 10.1016/S1476‑5586(03)80005‑2 12659686
    [Google Scholar]
  97. Cheng H. Qiu Y. Xu Y. Chen L. Ma K. Tao M. Frankiw L. Yin H. Xie E. Pan X. Du J. Wang Z. Zhu W. Chen L. Zhang L. Li G. Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness. Nat. Metab. 2023 5 2 314 330 10.1038/s42255‑022‑00730‑6 36717749
    [Google Scholar]
  98. Bosticardo M. Ariotti S. Losana G. Bernabei P. Forni G. Novelli F. Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation. Eur. J. Immunol. 2001 31 9 2829 2838 10.1002/1521‑4141(200109)31:9<2829:AID‑IMMU2829>3.0.CO;2‑U 11536182
    [Google Scholar]
  99. Ascic E. Åkerström F. Sreekumar Nair M. Rosa A. Kurochkin I. Zimmermannova O. Catena X. Rotankova N. Veser C. Rudnik M. Ballocci T. Schärer T. Huang X. de Rosa Torres M. Renaud E. Velasco Santiago M. Met Ö. Askmyr D. Lindstedt M. Greiff L. Ligeon L.A. Agarkova I. Svane I.M. Pires C.F. Rosa F.F. Pereira C.F. In vivo dendritic cell reprogramming for cancer immunotherapy. Science 2024 386 6719 eadn9083 10.1126/science.adn9083 39236156
    [Google Scholar]
  100. Kozlova N. Grossman J.E. Iwanicki M.P. Muranen T. The interplay of the extracellular matrix and stromal cells as a drug target in stroma-rich cancers. Trends Pharmacol. Sci. 2020 41 3 183 198 10.1016/j.tips.2020.01.001 32014341
    [Google Scholar]
  101. Zahavi D. Weiner L. Monoclonal antibodies in cancer therapy. Antibodies 2020 9 3 34 10.3390/antib9030034 32698317
    [Google Scholar]
  102. Sulea T. Rohani N. Baardsnes J. Corbeil C.R. Deprez C. Cepero-Donates Y. Robert A. Schrag J.D. Parat M. Duchesne M. Jaramillo M.L. Purisima E.O. Zwaagstra J.C. Structure-based engineering of pH-dependent antibody binding for selective targeting of solid-tumor microenvironment. MAbs 2020 12 1 1682866 10.1080/19420862.2019.1682866 31777319
    [Google Scholar]
  103. Goulet D.R. Atkins W.M. Considerations for the design of antibody-based therapeutics. J. Pharm. Sci. 2020 109 1 74 103 10.1016/j.xphs.2019.05.031 31173761
    [Google Scholar]
  104. Hoffman W.L. Jump A.A. Kelly P.J. Ruggles A.O. Binding of antibodies and other proteins to nitrocellulose in acidic, basic, and chaotropic buffers. Anal. Biochem. 1991 198 1 112 118 10.1016/0003‑2697(91)90514‑T 1789412
    [Google Scholar]
  105. Zhang Y.X. Zhao Y.Y. Shen J. Sun X. Liu Y. Liu H. Wang Y. Wang J. Nanoenabled modulation of acidic tumor microenvironment reverses anergy of infiltrating t cells and potentiates anti-PD-1 therapy. Nano Lett. 2019 19 5 2774 2783 10.1021/acs.nanolett.8b04296 30943039
    [Google Scholar]
  106. 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 4 450 10.3390/cancers11040450 30934955
    [Google Scholar]
  107. Wei Y. Xu H. Dai J. Peng J. Wang W. Xia L. Zhou F. Prognostic significance of serum lactic acid, lactate dehydrogenase, and albumin levels in patients with metastatic colorectal cancer. BioMed Res. Int. 2018 2018 1 8 10.1155/2018/1804086 30627541
    [Google Scholar]
  108. Chao M. Wu H. Jin K. Li B. Wu J. Zhang G. Yang G. Hu X. A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis. eLife 2016 5 15691 10.7554/eLife.15691 27481188
    [Google Scholar]
  109. Wang Q.Z. Chen X.P. Huang J.P. Jiang X.W. Effects of couplet medicines (astragalus membranaceus and jiaozhen) on intestinal barrier in postoperative colorectal cancer patients Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 2015 35 11 1307 1312 26775475
    [Google Scholar]
  110. Jansen T.C. van Bommel J. Schoonderbeek F.J. Sleeswijk Visser S.J. van der Klooster J.M. Lima A.P. Willemsen S.P. Bakker J. Early lactate-guided therapy in intensive care unit patients: A multicenter, open-label, randomized controlled trial. Am. J. Respir. Crit. Care Med. 2010 182 6 752 761 10.1164/rccm.200912‑1918OC 20463176
    [Google Scholar]
  111. Thompson J.J. McGovern J. Roxburgh C.S.D. Edwards J. Dolan R.D. McMillan D.C. The relationship between LDH and GLIM criteria for cancer cachexia: Systematic review and meta-analysis. Crit. Rev. Oncol. Hematol. 2024 199 104378 10.1016/j.critrevonc.2024.104378 38754770
    [Google Scholar]
  112. Amaravadi R.K. Clinical trial results show promise of targeting autophagy BRAF mutant melanoma. Autophagy 2022 18 6 1470 1471 10.1080/15548627.2022.2038899 35156519
    [Google Scholar]
  113. Nosrati A. Tsai K.K. Goldinger S.M. Tumeh P. Grimes B. Loo K. Algazi A.P. Nguyen-Kim T.D.L. Levesque M. Dummer R. Hamid O. Daud A. Evaluation of clinicopathological factors in PD-1 response: Derivation and validation of a prediction scale for response to PD-1 monotherapy. Br. J. Cancer 2017 116 9 1141 1147 10.1038/bjc.2017.70 28324889
    [Google Scholar]
  114. Labgaa I. Joliat G.R. Kefleyesus A. Mantziari S. Schäfer M. Demartines N. Hübner M. Is postoperative decrease of serum albumin an early predictor of complications after major abdominal surgery? A prospective cohort study in a European centre. BMJ Open 2017 7 4 013966 10.1136/bmjopen‑2016‑013966 28391235
    [Google Scholar]
  115. Zhou J. Shao Q. Lu Y. Li Y. Xu Z. Zhou B. Chen Q. Li X. Xu X. Pan Y. Deng Z. Wang Y. Yu Y. Gu J. Monocarboxylate transporter upregulation in induced regulatory T cells promotes resistance to anti-PD-1 therapy in hepatocellular carcinoma patients. Front. Oncol. 2022 12 960066 10.3389/fonc.2022.960066 35965549
    [Google Scholar]
  116. Gao T. Lin Y.Q. Ye H.Y. Lin W.M. miR-124 delivered by BM-MSCs-derived exosomes targets MCT1 of tumor-infiltrating Treg cells and improves ovarian cancer immunotherapy. Neoplasma 2024 70 6 713 721 10.4149/neo_2023_230711N362 37962863
    [Google Scholar]
  117. Duan X. Xie Y. Yu J. Hu X. Liu Z. Li N. Qin J. Lan L. Yuan M. Pan Z. Wang Y. MCT4/lactate promotes PD-L1 glycosylation in triple-negative breast cancer cells. J. Oncol. 2022 2022 1 15 10.1155/2022/3659714 36199799
    [Google Scholar]
  118. Wang S. Ma L. Wang Z. He H. Chen H. Duan Z. Li Y. Si Q. Chuang T.H. Chen C. Luo Y. Lactate dehydrogenase-A (LDH-A) preserves cancer stemness and recruitment of tumor-associated macrophages to promote breast cancer progression. Front. Oncol. 2021 11 654452 10.3389/fonc.2021.654452 34178639
    [Google Scholar]
  119. Giatromanolaki A. Gkegka A.G. Pouliliou S. Biziota E. Kakolyris S. Koukourakis M. Hypoxia and anaerobic metabolism relate with immunologically cold breast cancer and poor prognosis. Breast Cancer Res. Treat. 2022 194 1 13 23 10.1007/s10549‑022‑06609‑0 35482128
    [Google Scholar]
  120. Li S. Zhao C. Gao J. Zhuang X. Liu S. Xing X. Liu Q. Chen C. Wang S. Luo Y. Cyclin G2 reverses immunosuppressive tumor microenvironment and potentiates PD-1 blockade in glioma. J. Exp. Clin. Cancer Res. 2021 40 1 273 10.1186/s13046‑021‑02078‑3 34452627
    [Google Scholar]
  121. Zhang Y.T. Xing M.L. Fang H.H. Li W.D. Wu L. Chen Z.P. Effects of lactate on metabolism and differentiation of CD4+T cells. Mol. Immunol. 2023 154 96 107 10.1016/j.molimm.2022.12.015 36621062
    [Google Scholar]
  122. Li N. Kang Y. Wang L. Huff S. Tang R. Hui H. Agrawal K. Gonzalez G.M. Wang Y. Patel S.P. Rana T.M. ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment. Proc. Natl. Acad. Sci. USA 2020 117 33 20159 20170 10.1073/pnas.1918986117 32747553
    [Google Scholar]
  123. Silva A. Antunes B. Batista A. Pinto-Ribeiro F. Baltazar F. Afonso J. In vivo anticancer activity of AZD3965: A systematic review. Molecules 2021 27 1 181 10.3390/molecules27010181 35011413
    [Google Scholar]
  124. Shi S. Li J. Zhou X. Li Z. Wang Y. Xu B. Ye S. Transport mechanism and drug discovery of human monocarboxylate transporter 1. Acta Pharmacol. Sin. 2025 1 6 10.1038/s41401‑025‑01517‑7 40097709
    [Google Scholar]
  125. Powell S.F. Mazurczak M. Dib E.G. Bleeker J.S. Geeraerts L.H. Tinguely M. Lohr M.M. McGraw S.C. Jensen A.W. Ellison C.A. Black L.J. Puumala S.E. Reed V.J. Miskimins W.K. Lee J.H. Spanos W.C. Phase II study of dichloroacetate, an inhibitor of pyruvate dehydrogenase, in combination with chemoradiotherapy for unresected, locally advanced head and neck squamous cell carcinoma. Invest. New Drugs 2022 40 3 622 633 10.1007/s10637‑022‑01235‑5 35312941
    [Google Scholar]
  126. Renner K. Bruss C. Schnell A. Koehl G. Becker H.M. Fante M. Menevse A.N. Kauer N. Blazquez R. Hacker L. Decking S.M. Bohn T. Faerber S. Evert K. Aigle L. Amslinger S. Landa M. Krijgsman O. Rozeman E.A. Brummer C. Siska P.J. Singer K. Pektor S. Miederer M. Peter K. Gottfried E. Herr W. Marchiq I. Pouyssegur J. Roush W.R. Ong S. Warren S. Pukrop T. Beckhove P. Lang S.A. Bopp T. Blank C.U. Cleveland J.L. Oefner P.J. 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 10.1016/j.celrep.2019.08.068 31577944
    [Google Scholar]
  127. Dunbar E.M. Coats B.S. Shroads A.L. Langaee T. Lew A. Forder J.R. Shuster J.J. Wagner D.A. Stacpoole P.W. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest. New Drugs 2014 32 3 452 464 10.1007/s10637‑013‑0047‑4 24297161
    [Google Scholar]
  128. Raez L.E. Papadopoulos K. Ricart A.D. Chiorean E.G. DiPaola R.S. Stein M.N. Rocha Lima C.M. Schlesselman J.J. Tolba K. Langmuir V.K. Kroll S. Jung D.T. Kurtoglu M. Rosenblatt J. Lampidis T.J. A phase I dose-escalation trial of 2-deoxy-d-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 2013 71 2 523 530 10.1007/s00280‑012‑2045‑1 23228990
    [Google Scholar]
  129. Noble R.A. Bell N. Blair H. Sikka A. Thomas H. Phillips N. Nakjang S. Miwa S. Crossland R. Rand V. Televantou D. Long A. Keun H.C. Bacon C.M. Bomken S. Critchlow S.E. Wedge S.R. Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma. Haematologica 2017 102 7 1247 1257 10.3324/haematol.2016.163030 28385782
    [Google Scholar]
  130. Flaig T.W. Glodé M. Gustafson D. van Bokhoven A. Tao Y. Wilson S. Su L.J. Li Y. Harrison G. Agarwal R. Crawford E.D. Lucia M.S. Pollak M. A study of high‐dose oral silybin‐phytosome followed by prostatectomy in patients with localized prostate cancer. Prostate 2010 70 8 848 855 10.1002/pros.21118 20127732
    [Google Scholar]
  131. Klotz S. Kaufmann N. Kuenz A. Prüße U. Biotechnological production of enantiomerically pure d-lactic acid. Appl. Microbiol. Biotechnol. 2016 100 22 9423 9437 10.1007/s00253‑016‑7843‑7 27654657
    [Google Scholar]
  132. Pohanka M. D‐lactic acid as a metabolite: Toxicology, diagnosis, and detection. BioMed Res. Int. 2020 2020 1 3419034 10.1155/2020/3419034 32685468
    [Google Scholar]
  133. Chen J. Huang Z. Chen Y. Tian H. Chai P. Shen Y. Yao Y. Xu S. Ge S. Jia R. Lactate and lactylation in cancer. Signal Transduct. Target. Ther. 2025 10 1 38 10.1038/s41392‑024‑02082‑x 39934144
    [Google Scholar]
  134. Singh M. Afonso J. Sharma D. Gupta R. Kumar V. Rani R. Baltazar F. Kumar V. Targeting monocarboxylate transporters (MCTs) in cancer: How close are we to the clinics? Semin. Cancer Biol. 2023 90 1 14 10.1016/j.semcancer.2023.01.007 36706846
    [Google Scholar]
  135. Li X. Zhang Y. Xu L. Wang A. Zou Y. Li T. Huang L. Chen W. Liu S. Jiang K. Zhang X. Wang D. Zhang L. Zhang Z. Zhang Z. Chen X. Jia W. Zhao A. Yan X. Zhou H. Zhu L. Ma X. Ju Z. Jia W. Wang C. Loscalzo J. Yang Y. Zhao Y. Ultrasensitive sensors reveal the spatiotemporal landscape of lactate metabolism in physiology and disease. Cell Metab. 2023 35 1 200 211.e9 10.1016/j.cmet.2022.10.002 36309010
    [Google Scholar]
  136. Hu Y. Gao S. Lu H. Ying J.Y. Acid-resistant and physiological ph-responsive dna hydrogel composed of a-motif and i-motif toward oral insulin delivery. J. Am. Chem. Soc. 2022 144 12 5461 5470 10.1021/jacs.1c13426 35312303
    [Google Scholar]
  137. Gao Y. Zhou H. Liu G. Wu J. Yuan Y. Shang A. Tumor microenvironment: Lactic acid promotes tumor development. J. Immunol. Res. 2022 2022 1 8 10.1155/2022/3119375 35733921
    [Google Scholar]
  138. Wang J.X. Choi S.Y.C. Niu X. Kang N. Xue H. Killam J. Wang Y. Lactic acid and an acidic tumor microenvironment suppress anticancer immunity. Int. J. Mol. Sci. 2020 21 21 8363 10.3390/ijms21218363 33171818
    [Google Scholar]
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  • Article Type:
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Keywords: immunotherapy ; immune ; lactic acid ; Lactate ; tumor ; cancer
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