Fig. 2.

Immune modulation by lactate in the tumour microenvironment. The tumour microenvironment (TME) is filled with multiple cell populations, including tumour, stromal, and immune cells, as well as vascular endothelial cells. In the TME, tumour cells consume most of the nutrients and secrete excessive lactate into the extracellular microenvironment, resulting in acidosis, angiogenesis and immunosuppression. Lactate also modulates the metabolism of innate and adaptive immune cells, by inhibiting the functions of CD8⁺ T cells, natural killer (NK) cells, natural killer T (NKT) cells and dendritic cells. By contrast, lactate favours FOXP3⁺ regulatory T (Treg) cells sustaining their immunosuppressive functions in the acidic environment. Additionally, lactate potentiates the M2 polarization of alternatively activated macrophages, promoting angiogenesis and tumorigenesis. Summarily, lactate plays a pro-oncogenic role in the TME. CAFs, cancer-associated fibroblasts; ERK, extracellular regulated protein kinases; FOXP3, forkhead box protein 3; GPR132, G-protein-coupled receptor 132; GPR81, Gi-protein-coupled receptor 81; HDAC, histone deacetylase; HIF-1α, hypoxia-inducible factor 1α; mTOR, mechanistic target of rapamycin; MCT, monocarboxylate transporter; NFAT, nuclear factor of activated T cells; PPARγ, peroxisome proliferator-activated receptor γ; STAT3, signal transducer and activator of transcription 3; SREBF1, sterol regulatory element-binding transcription factor 1; TAMs, tumour-associated macrophages; VEGF, vascular endothelial growth factor. Zi-Hao Wang and Qiong Zhou design this figure. All authors confirm originality of it and retain copyright to it.