Lactate Metabolism and Immune Microenvironment Dynamics

Lactate has emerged from its classical designation as a metabolic by-product to a pivotal signalling mediator that shapes the immune microenvironment. Generated by glycolytic pathways in both tumours and sites of inflammation, lactate accumulation influences the behaviour of innate and adaptive immune cells. Within tumours, elevated lactate contributes to extracellular acidification, suppressing cytotoxic lymphocytes, polarising macrophages towards immunosuppressive phenotypes and recruiting regulatory cell subsets. Similarly, in inflamed tissues, lactate modulates T cell retention and effector functions through transporter-dependent uptake, redirecting metabolic programmes towards fatty acid synthesis and shaping cytokine profiles. Crosstalk between lactate-producing cells and endothelial barriers further regulates leukocyte trafficking. The dynamic interplay between metabolic reprogramming and immune cell phenotypes underpins tumour progression, chronic inflammation and host defence, making lactate metabolism a compelling target for therapeutic modulation.

Research from Nature Portfolio

Recent studies have uncovered a metabolic dialogue between bone marrow neutrophils and the vascular endothelium mediated by lactate and its cognate receptor. In response to bacterial challenge, neutrophils amplify glycolysis and release lactate into the marrow microvasculature. This lactate engages GPR81 on endothelial cells to downregulate VE-cadherin, increase vascular permeability and promote neutrophil egress into the circulation. Genetic ablation of GPR81 or blockade of VE-cadherin rescues neutrophil release, revealing a lactate-driven axis critical for early host defence.

Lactate Metabolism and Immune Microenvironment Dynamics publication trend

The graph below shows the total number of articles in lactate metabolism and immune microenvironment dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Lactate: The end product of glycolysis that acts as a signalling metabolite in immune and stromal cells.

Tumour microenvironment (TME): The cellular and molecular milieu surrounding tumour cells, including immune, stromal and vascular components.

Monocarboxylate transporter (MCT): A family of membrane proteins that mediate lactate and proton exchange across cell membranes.

GPR81: A G protein-coupled receptor that senses extracellular lactate and transduces metabolic signals.

Epithelial–mesenchymal transition (EMT): A cellular programme in which epithelial cells acquire mesenchymal traits, enhancing motility and invasiveness.

References

1. Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions. PLOS Biology (2015).
2. Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling. Nature Communications (2020).
3. Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery. Journal of Experimental & Clinical Cancer Research (2023).
4. Role of Lactate in Inflammatory Processes: Friend or Foe. Frontiers in Immunology (2022).
5. Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma. Cancers (2019).
6. Metabolic Symbiosis and Immunomodulation: How Tumor Cell-Derived Lactate May Disturb Innate and Adaptive Immune Responses. Frontiers in Oncology (2018).