Although immunotherapy plays a significant role in tumor therapy, its efficacy is impaired by an immunosuppressive tumor microenvironment. A molecule that contributes to the protumor microenvironment is the metabolic product lactate. Lactate is produced in large amounts by cancer cells in response to either hypoxia or pseudohypoxia, and its presence in excess alters the normal functioning of immune cells. A key enzyme involved in lactate metabolism is lactate dehydrogenase (LDH). Elevated baseline LDH serum levels are associated with poor outcomes of current anticancer (immune) therapies, especially in patients with melanoma. Therefore, targeting LDH and other molecules involved in lactate metabolism might improve the efficacy of immune therapies. This review summarizes current knowledge about lactate metabolism and its role in the tumor microenvironment. Based on that information, we develop a rationale for deploying drugs that target lactate metabolism in combination with immune checkpoint inhibitors to overcome lactate-mediated immune escape of tumor cells.
Long regarded as merely a metabolic waste product, there is now growing evidence that L-lactate produced in excess by cancer cells favors tumor growth and metastasis. L-Lactate exerts this tumorigenic effect, at least in part, by disrupting the normal antitumor function of certain immune cells to create an immunosuppressive tumor microenvironment. This has important therapeutic implications because the localized immunosuppression blunts the efficacy of anticancer immunotherapies. Thus, in principle, targeting lactate metabolism could be a strategy to bolster the effectiveness of cancer therapies and improve patient outcomes. Before delving into these therapeutic possibilities, we begin with an overview of lactate metabolism, especially as it relates to energy production in cancer cells.
Lactate (2-hydroxypropanoate) is a hydroxycarboxylic acid. Two stereoisomers exist, L-lactate and D-lactate. L-Lactate is the predominant enantiomer in the human body [
Different oxygen conditions determine the direction of the immune response in the tumor microenvironment. With increasing distance of tumor cells from blood vessels, the oxygen concentration drops. The tumor is not able to respire but instead uses primarily glycolysis for energy production with concomitant production of lactate, which in turn generates an immunosuppressive microenvironment that promotes tumor growth and metastasis (upper panel). Genetic alterations and high levels of lactate causing HIF-1
The Warburg effect describes the phenomenon, wherein cancer cells generate energy predominantly via glycolysis even if sufficient oxygen for respiration is present (Figure
In normal cells, one molecule of glucose produces 38 molecules of ATP during complete oxidation in mitochondria. In cancer cells, pyruvate oxidation is downregulated and replaced by lactate production, catalyzed by LDH, without ATP generation. Thus, in tumor cells, one molecule of glucose produces only two molecules of ATP [
In addition to the classic Warburg hypothesis, other models have been proposed. The two primary ones are the reverse Warburg effect and the lactate shuttle hypothesis (several additional models are more or less variations of these two hypotheses). An important feature of these two models is that they take into consideration cell-cell interactions, tumor microenvironment, and compartmentalization.
In 2009, a novel “two-compartment metabolic coupling” model, also named “the reverse Warburg effect,” was proposed [
The
A major player in the glycolytic response to hypoxia is the transcription factor hypoxia-inducible factor-1
A functioning OXPHOS system only makes sense if oxygen is present. Therefore, the majority of melanomas may be regarded as tumors that do not follow the classic Warburg rules. Several oxygen-independent pathways that regulate HIF-1
As early as 1954, increased levels of LDH were detected in serum of melanoma patients [
Lactate has begun to be recognized as an active molecule capable of modulating the immune response. Tumor-derived lactate modulates the functionality of immune cells, contributing to the establishment of an immunosuppressive microenvironment which favors the development of tumors [
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells and play a crucial role in mediating immunosuppressive effects in the tumor microenvironment [
Tumor-associated macrophages (TAMs) are one of the most abundant cells in the tumor stroma and contribute to tumor progression at different levels [
Some subsets of functionally distinct DC populations in the tumor microenvironment display a tolerogenic and immune suppressive phenotype [
Several studies demonstrate that lactate negatively affects tumor immunosurveillance by T cells. Lactate suppressed the proliferation and function of murine and human cytotoxic T lymphocytes (CTLs)
Murine tumors with reduced lactic acid production caused by
NK cells are part of the innate tumor immune surveillance system, but their contribution is diminished by the presence of lactic acid in an acidic tumor microenvironment [
Cancer-associated fibroblasts (CAFs) are a dynamic component of the tumor microenvironment. These cells modulate the interaction between tumor cells and the host stromal response, and CAF-associated metabolic reprogramming can facilitate tumor progression [
Endothelial cells are another cell type involved in the crosstalk with tumor cells in the tumor microenvironment [
Due to the multitude of effects of lactate in promoting immune evasion of tumors and stimulating tumor angiogenesis, targeting lactate metabolism in combination with immunotherapy is a promising approach to enhance the efficacy of immune therapies. This was recently demonstrated in a murine melanoma model, where blockage of LDHA not only increased the number of NK cells and CTLs but also augmented their cytolytic activity, resulting in reduced melanoma growth in combination with antiprogrammed cell death protein-1 (PD-1) therapy in comparison with PD-1 therapy alone [
Although genetic disruption or silencing of LDHA was shown to inhibit tumor growth
Several LDH inhibitors have been tested preclinically for anticancer activity, but the majority of them have low potency and off-target effects and therefore are not suitable for clinical use [
Oxamate, a known LDH inhibitor for more than 60 years [
Quinoline-3-sulfonamides have been shown to have antitumor activity, but their clinical use is hampered by their poor bioavailability [
A 2-amino-5-aryl pyrazine and a 2-thio-6-oxo-1,6-dihydropyrimidine were identified as potent inhibitors of human LDH, but they showed only minimal cellular activity in cancer cells [
Other drugs which target LDH by different mechanisms and exhibit preclinical antiproliferative activity against cancer cell lines, such as galloflavin [
Recently, molecules with 1,4-triazole moieties have been reported as potent inhibitors of LDH, but they have not been tested for anticancer activity [
Several natural products, including the saffron derivative crocetin, have been identified as LDH inhibitors with antiproliferative activity against cancer cell lines [
Gossypol (also known as AT-101), derived from cotton plant seeds, is a nonselective inhibitor of LDH whose antitumor activity has been attributed to its additional capability to inhibit the antiapoptotic Bcl-2 protein family [
Oroxylin A, a bioactive flavonoid isolated from a Chinese medicinal plant, inhibited LDH and the production of lactate in human hepatocellular carcinoma cells [
A recent high-throughput screen of 1280 drugs identified vitamin C as an LDH-lowering agent, which reduced lactate production and inhibited tumor growth of breast cancer cells in a chronic stress model [
There are several drugs currently approved for clinical use which could potentially be repurposed as LDH inhibitors such as the antiepileptic drug stiripentol [
As knockdown of the lactate transporters MCT1 and MCT4 resulted in suppression of breast cancer and colorectal cancer
For MCT4, diclofenac [
GPR81 (HCAR-1) is a lactate-sensing receptor found on monocytes and other immune cells [
The Warburg effect and altered tumor metabolism have been recognized as a hallmark of cancer for nearly a century. Lactate is one of the key “oncometabolites” regulating the interaction of cancer cells with the tumor microenvironment. Since elevated serum LDH is negatively associated with clinical efficacy of anticancer (immune) therapies, targeting this enzyme or other molecules involved in lactate metabolism clearly has potential to improve patient outcomes. Although several LDH inhibitors lack selectivity and clinical efficacy in monotherapy, there may be strong potential in combining them with immunotherapy, especially in patients with high LDH levels. Possible off-target effects (either beneficial or toxic) would need to be assessed. Repurposing of approved drugs which can inhibit LDH and have been well tolerated in clinical trials could circumvent toxicity concerns. Besides inhibition of LDH, there are other key molecules involved in lactate metabolism which could be targeted to overcome resistance to immune therapy.
Aspartate aminotransferase
American Joint Committee on Cancer
Protein kinase B
Adenosine triphosphate
B cell lymphoma 2
v-Raf murine sarcoma viral oncogene homolog B
Cancer-associated fibroblast
Carbonic anhydrase IX
Cyclooxygenase 2
Cytotoxic T lymphocyte
Cytotoxic T-lymphocyte-associated protein 4
Dendritic cell
G-protein coupled receptor 81
G-protein coupled receptor 132
Hydroxycarboxylic acid receptor 1
Hypoxia-inducible factor-1
Human umbilical vein endothelial cell
Interferon-
Intermembrane space
Lactate dehydrogenase
Lipopolysaccharide
Monocarboxylate transporter 1
Monocarboxylate transporter 2
Monocarboxylate transporter 4
Myeloid-derived suppressor cell
Microphthalmia-associated transcription factor
Nicotinamide adenine dinucleotide
Nuclear factor of activated T cells
Nuclear factor “kappa-light-chain-enhancer” of activated B cells
Natural killer cell
Natural killer group 2 member D
Overall survival
Oxidative phosphorylation
Programmed cell death protein 1
Progression-free survival
Reactive oxygen species
Solute carrier family 25 member 11 (malate-
Solute carrier family 25 member 12 (glutamate aspartate antiporter)
Solute carrier family 25 member 13 (glutamate aspartate antiporter)
Sodium-coupled monocarboxylate transporter 1
Sodium-coupled monocarboxylate transporter 2
Tumor-associated macrophage
Vascular endothelial growth factor
von Hippel Lindau.
The authors declare that they have no conflicts of interest.