Innate lymphoid cells and tumor-derived lactic acid: novel contenders in an enduring game

Abstract

Aerobic glycolysis, also known as the Warburg effect, has for a prolonged period of time been perceived as a defining feature of tumor metabolism. The redirection of glucose utilization towards increased production of lactate by cancer cells enables their rapid proliferation, unceasing growth, and longevity. At the same time, it serves as a significant contributor to acidification of the tumor microenvironment, which, in turn, imposes substantial constraints on infiltrating immune cells. Here, we delve into the influence of tumor-derived lactic acid on innate lymphoid cells (ILCs) and discuss potential therapeutic approaches. Given the abundance of ILCs in barrier tissues such as the skin, we provide insights aimed at translating this knowledge into therapies that may specifically target skin cancer.

Keywords: innate lymphoid cells; lactate; lactic acid; melanoma; metabolism; skin; skin cancer.

Figure 1

The Warburg effect and its impact on ILCs in the tumor microenvironment. The Warburg effect (or aerobic glycolysis) is characterized by a metabolic reprogramming in which cancer cells rely on glycolysis regardless of the availability of oxygen. In this process, most of the pyruvate generated from glucose undergoes glycolytic transformation, resulting in the production of lactate, protons, and ATP. Lactate and lactic acid contribute to acidification of the tumor environment, thereby disrupting the function of immune cells, including innate lymphoid cells (ILCs). Consequently, NK cells show reduced production of INF-γ and granzyme B, as well as significantly diminished survival. In T-bet⁺NK1.1^- ILC1-like cells, inhibition of proliferation and INF-γ secretion occurs accompanied by an increase in PD-1 expression and uptake of fatty acids. Negative effects are also observed in Sca1⁺KLRG1⁺ ILC2 cells, including impaired proliferation, decreased secretion of IL-5, and reduced survival. The impact of elevated PD-1 expression in ILC2s has yet to be fully understood. T-bet, T-box transcription factor; Sca1, stem cell antigen-1; KLRG1, killer cell lectin-like receptor subfamily G member 1; INF-γ, interferon gamma; PD-1, programmed cell death receptor 1. Figure created with BioRender.com.