Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
February-2025 Volume 31 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
February-2025 Volume 31 Issue 2

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Review Open Access

Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review)

  • Authors:
    • Yi Zeng
    • Yu Huang
    • Qiaoyun Tan
    • Ling Peng
    • Jian Wang
    • Fan Tong
    • Xiaorong Dong
  • View Affiliations / Copyright

    Affiliations: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
    Copyright: © Zeng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 48
    |
    Published online on: December 6, 2024
       https://doi.org/10.3892/mmr.2024.13413
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Metabolic reprogramming is a prominent characteristic of tumor cells, evidenced by heightened secretion of lactate, which is linked to tumor progression. Furthermore, the accumulation of lactate in the tumor microenvironment (TME) influences immune cell activity, including the activity of macrophages, dendritic cells and T cells, fostering an immunosuppressive milieu. Anti‑programmed cell death protein 1 (PD‑1)/programmed death‑ligand 1 (PD‑L1) therapy is associated with a prolonged survival time of patients with non‑small cell lung cancer. However, some patients still develop resistance to anti‑PD‑1/PD‑L1 therapy. Lactate is associated with resistance to anti‑PD‑1/PD‑L1 therapy. The present review summarizes what is known about lactate metabolism in tumor cells and how it affects immune cell function. In addition, the present review emphasizes the relationship between lactate secretion and immunotherapy resistance. The present review also explores the potential for targeting lactate within the TME to enhance the efficacy of immunotherapy.
View Figures

Figure 1

Figure 2

Figure 3

View References

1 

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 375:1823–1833. 2016. View Article : Google Scholar : PubMed/NCBI

2 

Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, et al: Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial. Lancet. 393:1819–1830. 2019. View Article : Google Scholar : PubMed/NCBI

3 

Lorusso D, Xiang Y, Hasegawa K, Scambia G, Leiva M, Ramos-Elias P, Acevedo A, Sukhin V, Cloven N, Pereira de Santana Gomes AJ, et al: Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): Overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 404:1321–1332. 2024. View Article : Google Scholar : PubMed/NCBI

4 

Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, Hajek J, Chang YH, Lee JL, Sarwar N, et al: Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 390:1359–1371. 2024. View Article : Google Scholar : PubMed/NCBI

5 

Yi M, Zheng X, Niu M, Zhu S, Ge H and Wu K: Combination strategies with PD-1/PD-L1 blockade: Current advances and future directions. Mol Cancer. 21:282022. View Article : Google Scholar : PubMed/NCBI

6 

Vesely MD, Zhang T and Chen L: Resistance mechanisms to anti-PD cancer immunotherapy. Annu Rev Immunol. 40:45–74. 2022. View Article : Google Scholar : PubMed/NCBI

7 

Peng DH, Rodriguez BL, Diao L, Chen L, Wang J, Byers LA, Wei Y, Chapman HA, Yamauchi M, Behrens C, et al: Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion. Nature Commun. 11:45202020. View Article : Google Scholar : PubMed/NCBI

8 

Yu M, Peng Z, Qin M, Liu Y, Wang J, Zhang C, Lin J, Dong T, Wang L, Li S, et al: Interferon-γ induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation. Mol Cell. 81:1216–1230.e9. 2021. View Article : Google Scholar : PubMed/NCBI

9 

Zhou X, Zou L, Liao H, Luo J, Yang T, Wu J, Chen W, Wu K, Cen S, Lv D, et al: Abrogation of HnRNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8+ T cell-mediated ferroptosis in castration-resistant prostate cancer. Acta Pharm Sin B. 12:692–707. 2022. View Article : Google Scholar : PubMed/NCBI

10 

Jiang Z, Lim SO, Yan M, Hsu JL, Yao J, Wei Y, Chang SS, Yamaguchi H, Lee HH, Ke B, et al: TYRO3 induces anti-PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis. J Clin Invest. 131:e1394342021. View Article : Google Scholar : PubMed/NCBI

11 

Zhou X, Lin J, Shao Y, Zheng H, Yang Y, Li S, Fan X, Hong H, Mao Z, Xue P, et al: Targeting PLCG2 suppresses tumor progression, orchestrates the tumor immune microenvironment and potentiates immune checkpoint blockade therapy for colorectal cancer. Int J Biol Sci. 20:5548–5575. 2024. View Article : Google Scholar : PubMed/NCBI

12 

Dai Y, Guo Z, Leng D, Jiao G, Chen K, Fu M, Liu Y, Shen Q, Wang Q, Zhu L and Zhao Q: Metal-coordinated NIR-II nanoadjuvants with nanobody conjugation for potentiating immunotherapy by tumor metabolism reprogramming. Adv Sci (Weinh). 11:e24048862024. View Article : Google Scholar : PubMed/NCBI

13 

Pavlova Natalya N and Thompson Craig B: The emerging hallmarks of cancer metabolism. Cell Metab. 23:27–47. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Nisar H, Sanchidrián González PM, Brauny M, Labonté FM, Schmitz C, Roggan MD, Konda B and Hellweg CE: Hypoxia changes energy metabolism and growth rate in non-small cell lung cancer cells. Cancers (Basel). 15:24722023. View Article : Google Scholar : PubMed/NCBI

15 

Li X, Wenes M, Romero P, Huang SCC, Fendt SM and Ho PC: Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat Rev Clin Oncol. 16:425–441. 2019. View Article : Google Scholar : PubMed/NCBI

16 

Zhang Y, Zhai Z, Duan J, Wang X, Zhong J, Wu L, Li A, Cao M, Wu Y, Shi H, et al: Lactate: The mediator of metabolism and immunosuppression. Front Endocrinol (Lausanne). 13:9014952022. View Article : Google Scholar : PubMed/NCBI

17 

Shergold AL, Millar R and Nibbs RJB: Understanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade. Pharmacol Res. 145:1042582019. View Article : Google Scholar : PubMed/NCBI

18 

Cao Z, Xu D, Harding J, Chen W, Liu X, Wang Z, Wang L, Qi T, Chen S, Guo X, et al: Lactate oxidase nanocapsules boost T cell immunity and efficacy of cancer immunotherapy. Sci Transl Med. 15:eadd27122023. View Article : Google Scholar : PubMed/NCBI

19 

Qian Y, Galan-Cobo A, Guijarro I, Dang M, Molkentine D, Poteete A, Zhang F, Wang Q, Wang J, Parra E, et al: MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma. Cancer Cell. 41:1363–1380.e7. 2023. View Article : Google Scholar : PubMed/NCBI

20 

Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, Gupta R, Tsai JM, Sinha R, Corey D, et al: PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 545:495–499. 2017. View Article : Google Scholar : PubMed/NCBI

21 

Marasco M, Berteotti A, Weyershaeuser J, Thorausch N, Sikorska J, Krausze J, Brandt HJ, Kirkpatrick J, Rios P, Schamel WW, et al: Molecular mechanism of SHP2 activation by PD-1 stimulation. Sci Adv. 6:eaay44582020. View Article : Google Scholar : PubMed/NCBI

22 

Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M and Saito T: Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 209:1201–1217. 2012. View Article : Google Scholar : PubMed/NCBI

23 

Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, Lindblad KE, Maier B, Sia D, Puigvehi M, Miguela V, Casanova-Acebes M, Dhainaut M, et al: β-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 9:1124–1141. 2019. View Article : Google Scholar : PubMed/NCBI

24 

Zhou L, Mudianto T, Ma X, Riley R and Uppaluri R: Targeting EZH2 enhances antigen presentation, antitumor Immunity, and circumvents anti-PD-1 resistance in head and neck cancer. Clin Cancer Res. 26:290–300. 2020. View Article : Google Scholar : PubMed/NCBI

25 

Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, Lund T, Tanić M, Reading JL, Joshi K, et al: Neoantigen-directed immune escape in lung cancer evolution. Nature. 567:479–485. 2019. View Article : Google Scholar : PubMed/NCBI

26 

Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJM, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 515:568–571. 2014. View Article : Google Scholar : PubMed/NCBI

27 

Kwon M, An M, Klempner SJ, Lee H, Kim KM, Sa JK, Cho HJ, Hong JY, Lee T, Min YW, et al: Determinants of response and intrinsic resistance to PD-1 blockade in microsatellite instability-high gastric cancer. Cancer Discov. 11:2168–2185. 2021. View Article : Google Scholar : PubMed/NCBI

28 

Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, Schrock AB, Hartmaier RJ, Trabucco SE, Gay L, et al: STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8:822–835. 2018. View Article : Google Scholar : PubMed/NCBI

29 

Messaoudene M, Pidgeon R, Richard C, Ponce M, Diop K, Benlaifaoui M, Nolin-Lapalme A, Cauchois F, Malo J, Belkaid W, et al: A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiota. Cancer Discov. 12:1070–1087. 2022. View Article : Google Scholar : PubMed/NCBI

30 

Lei Q, Wang D, Sun K, Wang L and Zhang Y: Resistance mechanisms of anti-PD1/PDL1 therapy in solid tumors. Front Cell Dev Biol. 8:6722020. View Article : Google Scholar : PubMed/NCBI

31 

Murciano-Goroff YR, Warner AB and Wolchok JD: The future of cancer immunotherapy: Microenvironment-targeting combinations. Cell Res. 30:507–519. 2020. View Article : Google Scholar : PubMed/NCBI

32 

Zou W and Green DR: Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy. Cell Metab. 35:1101–1113. 2023. View Article : Google Scholar : PubMed/NCBI

33 

Wang ZH, Peng WB, Zhang P, Yang XP and Zhou Q: Lactate in the tumour microenvironment: From immune modulation to therapy. EBioMedicine. 73:1036272021. View Article : Google Scholar : PubMed/NCBI

34 

Jedlička M, Feglarová T, Janstová L, Hortová-Kohoutková M and Frič J: Lactate from the tumor microenvironment-A key obstacle in NK cell-based immunotherapies. Front Immunol. 13:9320552022. View Article : Google Scholar : PubMed/NCBI

35 

Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, et al: Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 40:201–218.e9. 2022. View Article : Google Scholar : PubMed/NCBI

36 

Warburg O, Wind F and Negelein E: Über den stoffwechsel von tumoren im körper. Klin Wochenschr. 5:829–832. 1926. View Article : Google Scholar

37 

Paul S, Ghosh S and Kumar S: Tumor glycolysis, an essential sweet tooth of tumor cells. Semin Cancer Biol. 86:1216–1230. 2022. View Article : Google Scholar : PubMed/NCBI

38 

Luo B, Song L, Chen L, Cai Y, Zhang M and Wang S: Ganoderic acid D attenuates gemcitabine resistance of triple-negative breast cancer cells by inhibiting glycolysis via HIF-1alpha destabilization. Phytomedicine. 129:1556752024. View Article : Google Scholar : PubMed/NCBI

39 

Mossmann D, Park S and Hall MN: mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer. 18:744–757. 2018. View Article : Google Scholar : PubMed/NCBI

40 

Zhang P, Wan Y, Ma J, Gong J, Zhong Z, Cui Y, Zhang H, Da Y, Ma J, Li C, et al: Epigenetic silencing of LDHB promotes hepatocellular carcinoma by remodeling the tumor microenvironment. Cancer Immunol Immunother. 73:1272024. View Article : Google Scholar : PubMed/NCBI

41 

Hong SM, Lee YK, Park I, Kwon SM, Min S and Yoon G: Lactic acidosis caused by repressed lactate dehydrogenase subunit B expression down-regulates mitochondrial oxidative phosphorylation via the pyruvate dehydrogenase (PDH)-PDH kinase axis. J Biol Chem. 294:7810–7820. 2019. View Article : Google Scholar : PubMed/NCBI

42 

Yue J, Xu J, Yin Y, Shu Y, Li Y, Li T, Zou Z, Wang Z, Li F, Zhang M, et al: Targeting the PDK/PDH axis to reverse metabolic abnormalities by structure-based virtual screening with in vitro and in vivo experiments. Int J Biol Macromol. 262:1299702024. View Article : Google Scholar : PubMed/NCBI

43 

Li X, Yang Y, Zhang B, Lin X, Fu X, An Y, Zou Y, Wang JX, Wang Z and Yu T: Lactate metabolism in human health and disease. Signal Transduct Target Ther. 7:3052022. View Article : Google Scholar : PubMed/NCBI

44 

Tian LR, Lin MZ, Zhong HH, Cai YJ, Li B, Xiao ZC and Shuai XT: Nanodrug regulates lactic acid metabolism to reprogram the immunosuppressive tumor microenvironment for enhanced cancer immunotherapy. Biomater Sci. 10:3892–3900. 2022. View Article : Google Scholar : PubMed/NCBI

45 

Tasdogan A, Faubert B, Ramesh V, Ubellacker JM, Shen B, Solmonson A, Murphy MM, Gu Z, Gu W, Martin M, et al: Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature. 577:115–120. 2020. View Article : Google Scholar : PubMed/NCBI

46 

Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, Esparza LA, Reya T, Le Zhan, Yanxiang Guo J, et al: Glucose feeds the TCA cycle via circulating lactate. Nature. 551:115–118. 2017. View Article : Google Scholar : PubMed/NCBI

47 

Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, Yang C, Do QN, Doucette S, Burguete D, et al: Lactate metabolism in human lung tumors. Cell. 171:358–371.e9. 2017. View Article : Google Scholar : PubMed/NCBI

48 

Pérez-Escuredo J, Dadhich RK, Dhup S, Cacace A, Van Hée VF, De Saedeleer CJ, Sboarina M, Rodriguez F, Fontenille MJ, Brisson L, et al: Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle. 15:72–83. 2016. View Article : Google Scholar : PubMed/NCBI

49 

Gu J, Zhou J, Chen Q, Xu X, Gao J, Li X, Shao Q, Zhou B, Zhou H, Wei S, et al: Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells. Cell Rep. 39:1109862022. View Article : Google Scholar : PubMed/NCBI

50 

Ippolito L, Comito G, Parri M, Iozzo M, Duatti A, Virgilio F, Lorito N, Bacci M, Pardella E, Sandrini G, et al: Lactate rewires lipid metabolism and sustains a metabolic-epigenetic axis in prostate cancer. Cancer Res. 82:1267–1282. 2022. View Article : Google Scholar : PubMed/NCBI

51 

Xie D, Zhu S and Bai L: Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling. Sci China Life Sci. 59:1290–1296. 2016. View Article : Google Scholar : PubMed/NCBI

52 

Chen D, Liu P, Lu X, Li J, Qi D, Zang L, Lin J, Liu Y, Zhai S, Fu D, et al: Pan-cancer analysis implicates novel insights of lactate metabolism into immunotherapy response prediction and survival prognostication. J Exp Clin Cancer Res. 43:1252024. View Article : Google Scholar : PubMed/NCBI

53 

Marciscano AE and Anandasabapathy N: The role of dendritic cells in cancer and anti-tumor immunity. Semin Immunol. 52:1014812021. View Article : Google Scholar : PubMed/NCBI

54 

Christofides A, Strauss L, Yeo A, Cao C, Charest A and Boussiotis VA: The complex role of tumor-infiltrating macrophages. Nat Immunol. 23:1148–1156. 2022. View Article : Google Scholar : PubMed/NCBI

55 

Mu X, Shi W, Xu Y, Xu C, Zhao T, Geng B, Yang J, Pan J, Hu S, Zhang C, et al: Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle. 17:428–438. 2018. View Article : Google Scholar : PubMed/NCBI

56 

Zhang A, Xu Y, Xu H, Ren J, Meng T, Ni Y, Zhu Q, Zhang WB, Pan YB, Jin J, et al: Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17. Theranostics. 11:3839–3852. 2021. View Article : Google Scholar : PubMed/NCBI

57 

Chen P, Zuo H, Xiong H, Kolar MJ, Chu Q, Saghatelian A, Siegwart DJ and Wan Y: Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis. Proc Natl Acad Sci USA. 114:580–585. 2017. View Article : Google Scholar : PubMed/NCBI

58 

Jiang H, Wei H, Wang H, Wang Z, Li J, Ou Y, Xiao X, Wang W, Chang A, Sun W, et al: Zeb1-induced metabolic reprogramming of glycolysis is essential for macrophage polarization in breast cancer. Cell Death Dis. 13:2062022. View Article : Google Scholar : PubMed/NCBI

59 

Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, et al: Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 513:559–563. 2014. View Article : Google Scholar : PubMed/NCBI

60 

Cai J, Song L, Zhang F, Wu S, Zhu G, Zhang P, Chen S, Du J, Wang B, Cai Y, et al: Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma. Cancer Commun (Lond). 44:1231–1260. 2024. View Article : Google Scholar : PubMed/NCBI

61 

Zhang J, Muri J, Fitzgerald G, Gorski T, Gianni-Barrera R, Masschelein E, D'Hulst G, Gilardoni P, Turiel G, Fan Z, et al: Endothelial lactate controls muscle regeneration from ischemia by inducing M2-like macrophage polarization. Cell Metab. 31:1136–1153.e7. 2020. View Article : Google Scholar : PubMed/NCBI

62 

Morrissey SM, Zhang F, Ding C, Montoya-Durango DE, Hu X, Yang C, Wang Z, Yuan F, Fox M, Zhang HG, et al: Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming. Cell Metab. 33:2040–2058.e10. 2021. View Article : Google Scholar : PubMed/NCBI

63 

Tang H, Liang Y, Anders RA, Taube JM, Qiu X, Mulgaonkar A, Liu X, Harrington SM, Guo J, Xin Y, et al: PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J Clin Invest. 128:580–588. 2018. View Article : Google Scholar : PubMed/NCBI

64 

Del Prete A, Salvi V, Soriani A, Laffranchi M, Sozio F, Bosisio D and Sozzani S: Dendritic cell subsets in cancer immunity and tumor antigen sensing. Cell Mol Immunol. 20:432–447. 2023. View Article : Google Scholar : PubMed/NCBI

65 

See P, Dutertre CA, Chen J, Gunther P, McGovern N, Irac SE, Gunawan M, Beyer M, Händler K, Duan K, et al: Mapping the human DC lineage through the integration of high-dimensional techniques. Science. 356:eaag30092017. View Article : Google Scholar : PubMed/NCBI

66 

Rigamonti A, Villar J and Segura E: Monocyte differentiation within tissues: A renewed outlook. Trends Immunol. 44:999–1013. 2023. View Article : Google Scholar : PubMed/NCBI

67 

Peng X, He Y, Huang J, Tao Y and Liu S: Metabolism of dendritic cells in tumor microenvironment: for immunotherapy. Front Immunol. 12:6134922021. View Article : Google Scholar : PubMed/NCBI

68 

Monti M, Vescovi R, Consoli F, Farina D, Moratto D, Berruti A, Specchia C and Vermi W: Plasmacytoid dendritic cell impairment in metastatic melanoma by lactic acidosis. Cancers (Basel). 12:20852020. View Article : Google Scholar : PubMed/NCBI

69 

Brown TP, Bhattacharjee P, Ramachandran S, Sivaprakasam S, Ristic B, Sikder MOF and Ganapathy V: The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment. Oncogene. 39:3292–3304. 2020. View Article : Google Scholar : PubMed/NCBI

70 

Plebanek MP, Xue Y, Nguyen YV, DeVito NC, Wang X, Holtzhausen A, Beasley GM, Theivanthiran B and Hanks BA: A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression. Sci Immunol. 9:eadi41912024. View Article : Google Scholar : PubMed/NCBI

71 

Wang Z, Xu F, Hu J, Zhang H, Cui L, Lu W, He W, Wang X, Li M, Zhang H, et al: Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity. J Immunother Cancer. 9:e0021552021. View Article : Google Scholar : PubMed/NCBI

72 

Liu Y, Wang F, Peng D, Zhang D, Liu L, Wei J, Yuan J, Zhao L, Jiang H, Zhang T, et al: Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid. Sci Transl Med. 16:eadk73992024. View Article : Google Scholar : PubMed/NCBI

73 

Chen Y, Gao J, Ma M, Wang K, Liu F, Yang F, Yang F, Zou X, Cheng Z and Wu D: The potential role of CMC1 as an immunometabolic checkpoint in T cell immunity. Oncoimmunology. 13:23449052024. View Article : Google Scholar : PubMed/NCBI

74 

Sasaki K, Nishina S, Yamauchi A, Fukuda K, Hara Y, Yamamura M, Egashira K and Hino K: Nanoparticle-mediated delivery of 2-deoxy-D-glucose induces antitumor immunity and cytotoxicity in liver tumors in mice. Cell Mol Gastroenterol Hepatol. 11:739–762. 2021. View Article : Google Scholar : PubMed/NCBI

75 

Cappellesso F, Orban MP, Shirgaonkar N, Berardi E, Serneels J, Neveu MA, Di Molfetta D, Piccapane F, Caroppo R, Debellis L, et al: Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer. Nat Cancer. 3:1464–1483. 2022. View Article : Google Scholar : PubMed/NCBI

76 

Fang Y, Liu W, Tang Z, Ji X, Zhou Y, Song S, Tian M, Tao C, Huang R, Zhu G, et al: Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack. Hepatology. 77:109–123. 2023. View Article : Google Scholar : PubMed/NCBI

77 

Liu H, Liang Z, Cheng S, Huang L, Li W, Zhou C, Zheng X, Li S, Zeng Z and Kang L: Mutant KRAS drives immune evasion by sensitizing cytotoxic T-cells to activation-induced cell death in colorectal cancer. Adv Sci (Weinh). 10:e22037572023. View Article : Google Scholar : PubMed/NCBI

78 

Kaymak I, Luda KM, Duimstra LR, Ma EH, Longo J, Dahabieh MS, Faubert B, Oswald BM, Watson MJ, Kitchen-Goosen SM, et al: Carbon source availability drives nutrient utilization in CD8(+) T cells. Cell Metab. 34:1298–1311.e6. 2022. View Article : Google Scholar : PubMed/NCBI

79 

Notarangelo G, Spinelli JB, Perez EM, Baker GJ, Kurmi K, Elia I, Stopka SA, Baquer G, Lin JR, Golby AJ, et al: Oncometabolite d-2HG alters T cell metabolism to impair CD8(+) T cell function. Science. 377:1519–1529. 2022. View Article : Google Scholar : PubMed/NCBI

80 

Wang H, Grzywacz B, Sukovich D, McCullar V, Cao Q, Lee AB, Blazar BR, Cornfield DN, Miller JS and Verneris MR: The unexpected effect of cyclosporin A on CD56+CD16- and CD56+CD16+ natural killer cell subpopulations. Blood. 110:1530–1539. 2007. View Article : Google Scholar : PubMed/NCBI

81 

Miao L, Lu C, Zhang B, Li H, Zhao X, Chen H, Liu Y and Cui X: Advances in metabolic reprogramming of NK cells in the tumor microenvironment on the impact of NK therapy. J Transl Med. 22:2292024. View Article : Google Scholar : PubMed/NCBI

82 

Ge W, Meng L, Cao S, Hou C, Zhu X, Huang D, Li Q, Peng Y and Jiang K: The SIX1/LDHA axis promotes lactate accumulation and leads to NK cell dysfunction in pancreatic cancer. J Immunol Res. 2023:68916362023. View Article : Google Scholar : PubMed/NCBI

83 

Luo Z, Huang X, Xu X, Wei K, Zheng Y, Gong K and Li W: Decreased LDHB expression in breast tumor cells causes NK cell activation and promotes tumor progression. Cancer Biol Med. 21:513–540. 2024.PubMed/NCBI

84 

Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, et al: LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24:657–671. 2016. View Article : Google Scholar : PubMed/NCBI

85 

Abdolahi S, Ghazvinian Z, Muhammadnejad S, Ahmadvand M, Aghdaei HA, Ebrahimi-Barough S, Ai J, Zali MR, Verdi J and Baghaei K: Adaptive NK cell therapy modulated by anti-PD-1 antibody in gastric cancer model. Front Pharmacol. 12:7330752021. View Article : Google Scholar : PubMed/NCBI

86 

Sun Z, Tao W, Guo X, Jing C, Zhang M, Wang Z, Kong F, Suo N, Jiang S and Wang H: Construction of a lactate-related prognostic signature for predicting prognosis, tumor microenvironment, and immune response in kidney renal clear cell carcinoma. Front Immunol. 13:8189842022. View Article : Google Scholar : PubMed/NCBI

87 

Wagner NB, Forschner A, Leiter U, Garbe C and Eigentler TK: S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies. Br J Cancer. 119:339–346. 2018. View Article : Google Scholar : PubMed/NCBI

88 

Heuser C, Renner K, Kreutz M and Gattinoni L: Targeting lactate metabolism for cancer immunotherapy-a matter of precision. Semin Cancer Biol. 88:32–45. 2023. View Article : Google Scholar : PubMed/NCBI

89 

Ding Y, Yang J, Wei H, Wang J, Huang S, Yang S, Guo Y, Li B and Shuai X: Construction of pH-sensitive nanovaccines encapsulating tumor cell lysates and immune adjuvants for breast cancer therapy. Small. 19:e23014202023. View Article : Google Scholar : PubMed/NCBI

90 

Chen S, Zhou X, Yang X, Li W, Li S, Hu Z, Ling C, Shi R, Liu J, Chen G, et al: Dual blockade of lactate/GPR81 and PD-1/PD-L1 pathways enhances the anti-tumor effects of metformin. Biomolecules. 11:13732021. View Article : Google Scholar : PubMed/NCBI

91 

Ji P, Jin XK, Deng XC, Zhang SM, Liang JL, Li QR, Chen WH and Zhang XZ: Metabolic regulation-mediated reversion of the tumor immunosuppressive microenvironment for potentiating cooperative metabolic therapy and immunotherapy. Nano Lett. 24:4691–701. 2024. View Article : Google Scholar : PubMed/NCBI

92 

Renner K, Bruss C, Schnell A, Koehl G, Becker HM, Fante M, Menevse AN, Kauer N, Blazquez R, Hacker L, et al: Restricting glycolysis preserves T Cell effector functions and augments checkpoint therapy. Cell Rep. 29:135–150.e9. 2019. View Article : Google Scholar : PubMed/NCBI

93 

Zheng Y, Xu R, Chen X, Lu Y, Zheng J, Lin Y, Zheng J, Lin Y, Lin P, Zhao X and Cui L: Metabolic gatekeepers: Harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment. Cell Death Dis. 15:7752024. View Article : Google Scholar : PubMed/NCBI

94 

Liu Y, Zhao Y, Song H, Li Y, Liu Z, Ye Z, Zhao J, Wu Y, Tang J and Yao M: Metabolic reprogramming in tumor immune microenvironment: Impact on immune cell function and therapeutic implications. Cancer Lett. 597:2170762024. View Article : Google Scholar : PubMed/NCBI

95 

Li J, Zhao J, Tian C, Dong L, Kang Z, Wang J, Zhao S, Li M and Tong X: Mechanisms of regulation of glycolipid metabolism by natural compounds in plants: Effects on short-chain fatty acids. Nutr Metab (Lond). 21:492024. View Article : Google Scholar : PubMed/NCBI

96 

Wang J, Yang Y, Shao F, Meng Y, Guo D, He J and Lu Z: Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc. Nat Metab. 6:914–932. 2024. View Article : Google Scholar : PubMed/NCBI

97 

Bose S, Ramesh V and Locasale JW: Acetate metabolism in physiology, cancer, and beyond. Trends Cell Biol. 29:695–703. 2019. View Article : Google Scholar : PubMed/NCBI

98 

Burgdorf S, Porubsky S, Marx A and Popovic ZV: Cancer acidity and hypertonicity contribute to dysfunction of tumor-associated dendritic cells: Potential impact on antigen cross-presentation machinery. Cancers (Basel). 12:24032020. View Article : Google Scholar : PubMed/NCBI

99 

Shang S, Wang MZ, Xing Z, He N and Li S: Lactate regulators contribute to tumor microenvironment and predict prognosis in lung adenocarcinoma. Front Immunol. 13:10249252022. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Zeng Y, Huang Y, Tan Q, Peng L, Wang J, Tong F and Dong X: Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review). Mol Med Rep 31: 48, 2025.
APA
Zeng, Y., Huang, Y., Tan, Q., Peng, L., Wang, J., Tong, F., & Dong, X. (2025). Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review). Molecular Medicine Reports, 31, 48. https://doi.org/10.3892/mmr.2024.13413
MLA
Zeng, Y., Huang, Y., Tan, Q., Peng, L., Wang, J., Tong, F., Dong, X."Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review)". Molecular Medicine Reports 31.2 (2025): 48.
Chicago
Zeng, Y., Huang, Y., Tan, Q., Peng, L., Wang, J., Tong, F., Dong, X."Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review)". Molecular Medicine Reports 31, no. 2 (2025): 48. https://doi.org/10.3892/mmr.2024.13413
Copy and paste a formatted citation
x
Spandidos Publications style
Zeng Y, Huang Y, Tan Q, Peng L, Wang J, Tong F and Dong X: Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review). Mol Med Rep 31: 48, 2025.
APA
Zeng, Y., Huang, Y., Tan, Q., Peng, L., Wang, J., Tong, F., & Dong, X. (2025). Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review). Molecular Medicine Reports, 31, 48. https://doi.org/10.3892/mmr.2024.13413
MLA
Zeng, Y., Huang, Y., Tan, Q., Peng, L., Wang, J., Tong, F., Dong, X."Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review)". Molecular Medicine Reports 31.2 (2025): 48.
Chicago
Zeng, Y., Huang, Y., Tan, Q., Peng, L., Wang, J., Tong, F., Dong, X."Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review)". Molecular Medicine Reports 31, no. 2 (2025): 48. https://doi.org/10.3892/mmr.2024.13413
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team