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Peer-reviewedCC BY 4.0Metabolites

Lactate-Driven Biphasic Reprogramming of Macrophage Immune Responses

  • Qingshuang Guo1,2
  • Pan Ren3
  • Lanqi He2
  • Jiaying Gao2
  • Ruiqi Lu1
  • Yitian Wang4
  • Zhiheng Zhang4
  • Xiaohui Han1
  • Xi Zhang2
  • Chao Fang4
4 affiliations
  1. 1School of Medicine, Northwest University, Xi’an 710069, China
  2. 2Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
  3. 3Department of Burns, Plastic and Wound Repair Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710004, China
  4. 4Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an 710032, China
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Abstract

Lactate is a metabolic substrate, an extracellular signaling molecule, and a precursor for protein lactylation, with diverse effects on macrophage immunity. Evidence from infection, tissue injury, efferocytosis, and cancer indicates that lactate-associated pathways can amplify inflammation, support resolution and tissue repair, or sustain immune suppression. These outcomes depend on the timing, cellular source and compartment, chemical formulation and pH, transport and receptor engagement, and the chemistry and targets of lactylation. In this narrative review, we critically synthesize the biochemical foundations of lactate metabolism and lactyl-group donation and examine the mechanisms underlying these distinct macrophage responses. We distinguish model-specific biphasic responses from a universal sequence of early inflammation followed by resolution, and separate reparative programs from impaired antimicrobial or antitumor immunity. We also evaluate evidence for histone and non-histone lactylation, emphasizing the limits of metabolic perturbations and chromatin associations for establishing site-specific causality. This framework identifies experimental variables that should be controlled and supports context-selective investigation of lactate-related therapeutic targets in inflammatory diseases and cancer.

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Cite

BibTeXRIS
BibTeX
@article{guo2026lactatedriven,
  title = {{Lactate-Driven Biphasic Reprogramming of Macrophage Immune Responses}},
  author = {Qingshuang Guo and Pan Ren and Lanqi He and Jiaying Gao and Ruiqi Lu and Yitian Wang and Zhiheng Zhang and Xiaohui Han and Xi Zhang and Chao Fang},
  journal = {Metabolites},
  year = {2026},
  month = oct,
  doi = {10.3390/metabo16100788},
  url = {https://www.mdpi.com/2218-1989/16/10/788},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Lactate-Driven Biphasic Reprogramming of Macrophage Immune Responses
AU  - Qingshuang Guo
AU  - Pan Ren
AU  - Lanqi He
AU  - Jiaying Gao
AU  - Ruiqi Lu
AU  - Yitian Wang
AU  - Zhiheng Zhang
AU  - Xiaohui Han
AU  - Xi Zhang
AU  - Chao Fang
PY  - 2026
DA  - 2026/10/01
JO  - Metabolites
DO  - 10.3390/metabo16100788
UR  - https://www.mdpi.com/2218-1989/16/10/788
AB  - Lactate is a metabolic substrate, an extracellular signaling molecule, and a precursor for protein lactylation, with diverse effects on macrophage immunity. Evidence from infection, tissue injury, efferocytosis, and cancer indicates that lactate-associated pathways can amplify inflammation, support resolution and tissue repair, or sustain immune suppression. These outcomes depend on the timing, cellular source and compartment, chemical formulation and pH, transport and receptor engagement, and the chemistry and targets of lactylation. In this narrative review, we critically synthesize the biochemical foundations of lactate metabolism and lactyl-group donation and examine the mechanisms underlying these distinct macrophage responses. We distinguish model-specific biphasic responses from a universal sequence of early inflammation followed by resolution, and separate reparative programs from impaired antimicrobial or antitumor immunity. We also evaluate evidence for histone and non-histone lactylation, emphasizing the limits of metabolic perturbations and chromatin associations for establishing site-specific causality. This framework identifies experimental variables that should be controlled and supports context-selective investigation of lactate-related therapeutic targets in inflammatory diseases and cancer.
SN  - 2218-1989
ER  -