Lactate Contribution to the Tumor Microenvironment: Mechanisms, Effects on Immune Cells and Therapeutic Relevance

Abstract

Malignant transformation of cells leads to enhanced glucose uptake and the conversion of a larger fraction of pyruvate into lactate, even under normoxic conditions; this phenomenon of aerobic glycolysis is largely known as the Warburg effect. This metabolic reprograming serves to generate biosynthetic precursors, thus facilitating the survival of rapidly proliferating malignant cells. Extracellular lactate directs the metabolic reprograming of tumor cells, thereby serving as an additional selective pressure. Besides tumor cells, stromal cells are another source of lactate production in the tumor microenvironment, whose role in both tumor growth and the antitumor immune response is the subject of intense research. In this review, we provide an integral perspective of the relationship between lactate and the overall tumor microenvironment, from lactate structure to metabolic pathways for its synthesis, receptors, signaling pathways, lactate-producing cells, lactate-responding cells, and how all contribute to the tumor outcome. We discuss the role of lactate as an immunosuppressor molecule that contributes to tumor evasion and we explore the possibility of targeting lactate metabolism for cancer treatment, as well as of using lactate as a prognostic biomarker.

Keywords: Warburg effect; immune escape; l-lactate metabolism; monocarboxylate transporter; tumor microenvironment.

Figure 1

Lactate synthesis. ME, malic enzyme; MDH, malate dehydrogenase; LDH-A, lactate dehydrogenase A; GLS, glutaminase; GDH, glutamate dehydrogenase.

Figure 2

Impact of lactate on tumor microenvironment. Increased lactate secretion by tumor and stromal cells acidifies the tumor microenvironment, increases tumor cell survival and proliferation, stimulates angiogenesis, and results in skewed immune response by altering several immune infiltrating cells.