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Peer-reviewedCC BY-NC-NDSignal Transduction and Targeted Therapy

Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances

  • Chunyao Fang1
  • Suiqing Zhou1
  • Kai Yu1
  • Liren Zhang1
  • Wenxin Lian2
  • Xiaofeng Tie1
  • Shu Chen3
  • Jingjing Dai4
  • Qing Hao Li5
  • Xuehao Wang6,7
7 affiliations
  1. 1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing, China
  2. 2Department of Medical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
  3. 3Department of Hepatobiliary Pancreatic Spleen Surgery, The Affiliated Hospital of Jiangsu University, Zhenjiang, China
  4. 4Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. [email protected]
  5. 5Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing, China. [email protected]
  6. 6Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. [email protected]
  7. 7Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Jiangsu Provincial Medical Innovation Center, Jiangsu Provincial Medical Key Laboratory, Nanjing, China. [email protected]
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Abstract

Lactate and its mediated modification, lactylation, are receiving increasing attention in the field of tumor biology. This review provides a comprehensive overview of the mechanistic involvement of lactate and lactylation in key oncogenic processes, such as tumor initiation, proliferation, invasion, metastasis, recurrence, and drug resistance. Rather than being a passive byproduct of glycolysis, lactate actively shapes the tumor microenvironment (TME), modulates immune responses, drives metabolic adaptation, and influences epigenetic and transcriptomic regulation. Lactylation, as a novel epigenetic mechanism, links cellular metabolism with gene expression by modifying histone and nonhistone proteins, thereby regulating chromatin accessibility, immune evasion, and DNA repair. Notably, this article proposes a new perspective: lactate accumulation in certain tumors may constitute an adaptive metabolic strategy rather than a passive consequence of altered metabolism. This paradigm challenges the traditional perception of lactate as a metabolic waste, instead proposing its dual function as both a signaling molecule and a strategic modulator of tumor progression. The interplay of lactate-mediated signaling pathways, such as the PI3K/AKT, Hippo, Wnt, MAPK, and JAK/STAT pathways, further underscores the role of lactate in cancer progression. This review also explores therapeutic opportunities targeting lactate metabolism and lactylation, including inhibitors of LDH, MCTs, and lactylation-modifying enzymes, as well as the synergistic potential of combining lactate-targeted approaches with chemotherapy, immunotherapy, and targeted therapy. Overall, this review provides an integrative overview of lactate-mediated mechanisms and highlights their potential as targets for metabolism-oriented therapeutic interventions in oncology.

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Cite

BibTeXRIS
BibTeX
@article{fang2026lactate,
  title = {{Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances}},
  author = {Chunyao Fang and Suiqing Zhou and Kai Yu and Liren Zhang and Wenxin Lian and Xiaofeng Tie and Shu Chen and Jingjing Dai and Qing Hao Li and Xuehao Wang},
  journal = {Signal Transduction and Targeted Therapy},
  year = {2026},
  month = may,
  doi = {10.1038/s41392-026-02672-x},
  url = {https://doi.org/10.1038/s41392-026-02672-x},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Lactate metabolism and lactylation in cancer: from pathogenesis to therapeutic advances
AU  - Chunyao Fang
AU  - Suiqing Zhou
AU  - Kai Yu
AU  - Liren Zhang
AU  - Wenxin Lian
AU  - Xiaofeng Tie
AU  - Shu Chen
AU  - Jingjing Dai
AU  - Qing Hao Li
AU  - Xuehao Wang
PY  - 2026
DA  - 2026/05/21
JO  - Signal Transduction and Targeted Therapy
DO  - 10.1038/s41392-026-02672-x
UR  - https://doi.org/10.1038/s41392-026-02672-x
AB  - Lactate and its mediated modification, lactylation, are receiving increasing attention in the field of tumor biology. This review provides a comprehensive overview of the mechanistic involvement of lactate and lactylation in key oncogenic processes, such as tumor initiation, proliferation, invasion, metastasis, recurrence, and drug resistance. Rather than being a passive byproduct of glycolysis, lactate actively shapes the tumor microenvironment (TME), modulates immune responses, drives metabolic adaptation, and influences epigenetic and transcriptomic regulation. Lactylation, as a novel epigenetic mechanism, links cellular metabolism with gene expression by modifying histone and nonhistone proteins, thereby regulating chromatin accessibility, immune evasion, and DNA repair. Notably, this article proposes a new perspective: lactate accumulation in certain tumors may constitute an adaptive metabolic strategy rather than a passive consequence of altered metabolism. This paradigm challenges the traditional perception of lactate as a metabolic waste, instead proposing its dual function as both a signaling molecule and a strategic modulator of tumor progression. The interplay of lactate-mediated signaling pathways, such as the PI3K/AKT, Hippo, Wnt, MAPK, and JAK/STAT pathways, further underscores the role of lactate in cancer progression. This review also explores therapeutic opportunities targeting lactate metabolism and lactylation, including inhibitors of LDH, MCTs, and lactylation-modifying enzymes, as well as the synergistic potential of combining lactate-targeted approaches with chemotherapy, immunotherapy, and targeted therapy. Overall, this review provides an integrative overview of lactate-mediated mechanisms and highlights their potential as targets for metabolism-oriented therapeutic interventions in oncology.
SN  - 2059-3635
SN  - 2095-9907
ER  -