Lactate in the tumour microenvironment: From immune modulation to therapy

Abstract

Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in the tumour microenvironment (TME). Excessive lactate secreted by metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source by shuttling between different cell populations, and inhibiting the mechanistic (previously 'mammalian') target of rapamycin (mTOR) pathway in immune cells. This review focuses on recent advances in the regulation of immune responses by lactate, as well as therapeutic strategies targeting lactate anabolism and transport in the TME, such as those involving glycolytic enzymes and monocarboxylate transporter inhibitors. Considering the multifaceted roles of lactate in cancer metabolism, a comprehensive understanding of how lactate and lactate-targeting therapies regulate immune responses in the TME will provide insights into the complex relationships between metabolism and antitumour immunity.

Keywords: Cancer immunity; Cancer metabolism; Glycolytic enzymes; Lactate; Monocarboxylate transporters; Tumour microenvironment.

Fig. 1

Lactate from aerobic glycolysis and glutaminolysis in cancer cells. Aerobic glycolysis in cancer cells is efficient because of the cytoplasmic regeneration of NAD⁺ from NADH by LDHA without participating in mitochondrial electron transport chain. Without this process, deficiency of NAD⁺ pool limits glycolysis of cancer cells, then decreasing the rate of glycolysis at the GAPDH-mediated step. The continuous activation of HIF-1α, c-Myc, and the mTOR pathway induces aberrant expression of multiple glycolytic enzymes, thus facilitating aerobic glycolysis in cancer cells. ASCT2, alanine/serine/cysteine transporter 2; GLUT1, glucose transporter 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HIF-1α, hypoxia-inducible factor 1α; PFK-1, phosphofructokinase-1; MCT4, monocarboxylate transporter 4; mTOR, mechanistic target of rapamycin; LDHA, lactate dehydrogenase A. This figure is created by Pei Zhang, Zi-Hao Wang, and Qiong Zhou. All authors confirm originality of it and retain copyright to it.

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.

Fig. 3

Outstanding questions in lactate metabolism. This picture depicts the multi-faceted roles of lactate in the tumour microenvironment and provides a description of lactate-targeting therapies. This figure has not been published previously. Originality of it is confirmed by all authors.