Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Lactic acid induces dendritic cell pyroptosis through MCT-1 to promote tumor immune evasion

Oncogene (2026) Cite this article

Subjects

Abstract

Elevated metabolites in the tumor microenvironment (TME), particularly lactic acid, create an immunosuppressive milieu that promotes immune escape and tumor progression. Dendritic cells (DCs) are pivotal in initiating and regulating immune responses against tumors. However, the impact of lactic acid on DC death in the TME remains unclear. Our study reveals that lactic acid induces dose–dependent pyroptosis of bone marrow-derived DCs (BMDCs) through GSDMD cleavage. Mechanistically, this process involves monocarboxylate transporter 1(MCT1)-mediated signaling via the K+/NLRP3/GSDMD axis, facilitating immune evasion and cancer progression. Furthermore, inhibiting MCT1 attenuated lactic acid-induced DC pyroptosis both in vitro and in vivo. These findings offer mechanistic insights into how lactic acid-mediated DC pyroptosis contributes to tumor immune evasion, suggesting potential targets for enhancing cancer therapies.

The alternative text for this image may have been generated using AI.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Lactic acid induces DC pyroptosis in vitro.
The alternative text for this image may have been generated using AI.
Fig. 2: Inhibition of DC pyroptosis induced by tumor cell culture supernatant using MCT inhibitors.
The alternative text for this image may have been generated using AI.
Fig. 3: Lactic acid induces DC pyroptosis in vivo and promotes tumor growth.
The alternative text for this image may have been generated using AI.
Fig. 4: Lactic acid impairs the T cell priming function of DCs.
The alternative text for this image may have been generated using AI.
Fig. 5: Lactic acid induces DC pyroptosis through a K+/NLRP3/caspase-1/GSDMD axis.
The alternative text for this image may have been generated using AI.
Fig. 6: Blocking MCT1-mediated lactate influx attenuates DC pyroptosis.
The alternative text for this image may have been generated using AI.
Fig. 7: Lactic acid promotes tumor growth through MCT1 expression in DCs.
The alternative text for this image may have been generated using AI.
Fig. 8: Lactic acid induces human DC pyroptosis.
The alternative text for this image may have been generated using AI.

Similar content being viewed by others

Data availability

All data about this article were presented in the main body and the Supplementary Materials. Additional data related to this article can be requested from authors.

References

  1. Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res. 2019;79:4557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bader JE, Voss K, Rathmell JC. Targeting metabolism to improve the tumor microenvironment for cancer immunotherapy. Mol Cell. 2020;78:1019–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Liu Y, Wang F, Peng D, Zhang D, Liu L, Wei J, 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. 2024;16:eadk7399.

    Article  CAS  PubMed  Google Scholar 

  4. Zhou J, Gu J, Qian Q, Zhang Y, Huang T, Li X, et al. Lactate supports Treg function and immune balance via MGAT1 effects on N-glycosylation in the mitochondria. J Clin Invest. 2024;134:e175897.

  5. Damgaci S, Ibrahim-Hashim A, Enriquez-Navas PM, Pilon-Thomas S, Guvenis A, Gillies RJ. Hypoxia and acidosis: immune suppressors and therapeutic targets. Immunology. 2018;154:354–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. El-Kenawi A, Gatenbee C, Robertson-Tessi M, Bravo R, Dhillon J, Balagurunathan Y, et al. Acidity promotes tumour progression by altering macrophage phenotype in prostate cancer. Br J Cancer. 2019;121:556–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2020;20:7–24.

    Article  CAS  PubMed  Google Scholar 

  8. Gottfried E, Kunz-Schughart LA, Ebner S, Mueller-Klieser W, Hoves S, Andreesen R, et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood. 2006;107:2013–21.

    Article  CAS  PubMed  Google Scholar 

  9. Caronni N, Simoncello F, Stafetta F, Guarnaccia C, Ruiz-Moreno JS, Opitz B, et al. Downregulation of membrane trafficking proteins and lactate conditioning determine loss of dendritic cell function in lung cancer. Cancer Res. 2018;78:1685–99.

    Article  CAS  PubMed  Google Scholar 

  10. Plebanek MP, Xue Y, Nguyen YV, DeVito NC, Wang X, Holtzhausen A, et al. A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression. Sci Immunol. 2024;9:eadi4191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Monti M, Vescovi R, Consoli F, Farina D, Moratto D, Berruti A, et al. Plasmacytoid dendritic cell impairment in metastatic melanoma by lactic acidosis. Cancers.2020;12:2085.

  12. Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009;7:99–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016;535:111–6.

    Article  CAS  PubMed  Google Scholar 

  14. Hou J, Hsu JM, Hung MC. Molecular mechanisms and functions of pyroptosis in inflammation and antitumor immunity. Mol cell. 2021;81:4579–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sun S, Xu X, Liang L, Wang X, Bai X, Zhu L, et al. Lactic acid-producing probiotic saccharomyces cerevisiae attenuates ulcerative colitis via suppressing macrophage pyroptosis and modulating gut microbiota. Front Immunol. 2021;12:777665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. You X, Xie Y, Tan Q, Zhou C, Gu P, Zhang Y, et al. Glycolytic reprogramming governs crystalline silica-induced pyroptosis and inflammation through promoting lactylation modification. Ecotoxicol Environ Saf. 2024;283:116952.

    Article  CAS  PubMed  Google Scholar 

  17. Wang D, Gong Y, Chen Y, Wang Z, Yin J, Wang Z, et al. Lactate attenuates PANoptosis and enhances ZBP-1 lactylation in macrophages in acute lung injury. Front Immunol. 2025;16:1648303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhao K, An R, Xiang Q, Li G, Wang K, Song Y, et al. Acid-sensing ion channels regulate nucleus pulposus cell inflammation and pyroptosis via the NLRP3 inflammasome in intervertebral disc degeneration. Cell Prolif. 2021;54:e12941.

    Article  CAS  PubMed  Google Scholar 

  19. Li Z, Cui J. Targeting the lactic acid metabolic pathway for antitumor therapy. Mol Ther Oncolytics. 2023;31:100740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Halestrap AP. The monocarboxylate transporter family-Structure and functional characterization. IUBMB life. 2012;64:1–9.

    Article  CAS  PubMed  Google Scholar 

  21. Birnberg T, Bar-On L, Sapoznikov A, Caton ML, Cervantes-Barragan L, Makia D, et al. Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome. Immunity. 2008;29:986–97.

    Article  CAS  PubMed  Google Scholar 

  22. Downs KP, Nguyen H, Dorfleutner A, Stehlik C. An overview of the non-canonical inflammasome. Mol Asp Med. 2020;76:100924.

    Article  CAS  Google Scholar 

  23. Lagrange B, Benaoudia S, Wallet P, Magnotti F, Provost A, Michal F, et al. Human caspase-4 detects tetra-acylated LPS and cytosolic Francisella and functions differently from murine caspase-11. Nat Commun. 2018;9:242.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sutterwala FS, Haasken S, Cassel SL. Mechanism of NLRP3 inflammasome activation. Ann N Y Acad Sci. 2014;1319:82–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. He Y, Zeng MY, Yang D, Motro B, Núñez G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature. 2016;530:354–7.

    Article  CAS  PubMed  Google Scholar 

  26. Caton ML, Smith-Raska MR, Reizis B. Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen. J Exp Med. 2007;204:1653–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang JX, Choi SYC, Niu X, Kang N, Xue H, Killam J, et al. Lactic acid and an acidic tumor microenvironment suppress anticancer immunity. Int J Mol Sci.2020;21:8363.

  28. Kolb R, Phan L, Borcherding N, Liu Y, Yuan F, Janowski AM, et al. Obesity-associated NLRC4 inflammasome activation drives breast cancer progression. Nat Commun. 2016;7:13007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tu S, Bhagat G, Cui G, Takaishi S, Kurt-Jones EA, Rickman B, et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer cell. 2008;14:408–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mendoza-Rodríguez M, Arévalo Romero H, Fuentes-Pananá EM, Ayala-Sumuano JT, Meza I. IL-1β induces up-regulation of BIRC3, a gene involved in chemoresistance to doxorubicin in breast cancer cells. Cancer Lett. 2017;390:39–44.

    Article  PubMed  Google Scholar 

  31. Zhang J, Zhang Q, Lou Y, Fu Q, Chen Q, Wei T, et al. Hypoxia-inducible factor-1α/interleukin-1β signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment. Hepatology. 2018;67:1872–89.

    Article  CAS  PubMed  Google Scholar 

  32. Nakamura K, Kassem S, Cleynen A, Chrétien ML, Guillerey C, Putz EM, et al. Dysregulated IL-18 is a key driver of immunosuppression and a possible therapeutic target in the multiple myeloma microenvironment. Cancer cell. 2018;33:634–648.e635.

    Article  CAS  PubMed  Google Scholar 

  33. Terme M, Ullrich E, Aymeric L, Meinhardt K, Desbois M, Delahaye N, et al. IL-18 induces PD-1-dependent immunosuppression in cancer. Cancer Res. 2011;71:5393–9.

    Article  CAS  PubMed  Google Scholar 

  34. Novick D, Kim S, Kaplanski G, Dinarello CA. Interleukin-18, more than a Th1 cytokine. Semin Immunol. 2013;25:439–48.

    Article  CAS  PubMed  Google Scholar 

  35. Park S, Cheon S, Cho D. The dual effects of interleukin-18 in tumor progression. Cell Mol Immunol. 2007;4:329–35.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. Wang N, Jiang X, Zhang S, Zhu A, Yuan Y, Xu H, et al. Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Cell. 2021;184:370–383.e313.

    Article  CAS  PubMed  Google Scholar 

  38. 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 

  39. Noble RA, Bell N, Blair H, Sikka A, Thomas H, Phillips N, et al. Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma. Haematologica. 2017;102:1247–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Polański R, Hodgkinson CL, Fusi A, Nonaka D, Priest L, Kelly P, et al. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res. 2014;20:926–37.

    Article  PubMed  Google Scholar 

  41. Halford S, Veal GJ, Wedge SR, Payne GS, Bacon CM, Sloan P, et al. A phase I dose-escalation study of AZD3965, an oral monocarboxylate transporter 1 inhibitor, in patients with advanced cancer. Clin Cancer Res. 2023;29:1429–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr. Shuo Yang from Nanjing Medical University and Dr. Bingwei Wang from Nanjing University of Chinese Medicine for providing the B16F10 cell line and Gsdmd−/− mice. We also thank Dr. Yangxin Fu and Dr. Yong Liang from Tsinghua University for providing CD11c-DTR mice and Dr. Zhilin Hu from Nanjing Medical University for providing Mct1fl/fl Itgax-Cre mice.

Funding

This study was supported by the Jiangsu Province Capability Improvement Project through Science, Technology and Education (ZDXK202239), National Natural Science Foundation of China (no. 82103328), Jiangsu Province Maternal and Child Health Care Association Research Project (no. FYX202348), and Project of Zhenjiang City Social Development (SH2023046).

Author information

Author notes

  1. These authors contributed equally: Shengrui Yang, Liyuan Lin.

Authors and Affiliations

  1. Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Shengrui Yang, Liyuan Lin, Xiang Zheng, Jie Li, Rong Qin, Yuqing Wu & Jian Xu

  2. Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, China

    Shengrui Yang, Liyuan Lin, Xiang Zheng, Jie Li, Rong Qin, Yuqing Wu & Jian Xu

Authors
  1. Shengrui Yang
    View author publications

    Search author on:PubMed Google Scholar

  2. Liyuan Lin
    View author publications

    Search author on:PubMed Google Scholar

  3. Xiang Zheng
    View author publications

    Search author on:PubMed Google Scholar

  4. Jie Li
    View author publications

    Search author on:PubMed Google Scholar

  5. Rong Qin
    View author publications

    Search author on:PubMed Google Scholar

  6. Yuqing Wu
    View author publications

    Search author on:PubMed Google Scholar

  7. Jian Xu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Conceptualization, Jian Xu and Yuqing Wu; Methodology, Shengrui Yang, Yuqing Wu, Liyuan Lin and Xiang Zheng; Investigation, Liyuan Lin and Rong Qing; Resources, Jian Xu; Writing-Original Draft, Shengrui Yang and Liyuan Lin; Writing- Review & Editing, Shengrui Yang and Jie Li; Supervision, Jian Xu and Yuqing Wu; Funding Acquisition, Jian Xu, Yuqing Wu, and Rong Qing.

Corresponding authors

Correspondence to Yuqing Wu or Jian Xu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

This research was approved by the Research and Ethical Committee of the First Affiliated Hospital of Nanjing Medical University (2023-SR-637). The study protocol was conducted in accordance with the Declaration of Helsinki. All the animal experiments were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (approved number: 2207049). Mice were maintained in the Research Animal Support Facility, and all animal experiments were conducted according to the protocols approved by the Institutional Animal Care and Use Committee.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, S., Lin, L., Zheng, X. et al. Lactic acid induces dendritic cell pyroptosis through MCT-1 to promote tumor immune evasion. Oncogene (2026). https://doi.org/10.1038/s41388-026-03825-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41388-026-03825-6

Search

Advanced search

Quick links