The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment

Abstract

It is well known that tumor cells rely mainly on aerobic glycolysis for energy production even in the presence of oxygen, and glycolysis is a known modulator of tumorigenesis and tumor development. The tumor microenvironment (TME) is composed of tumor cells, various immune cells, cytokines, and extracellular matrix, among other factors, and is a complex niche supporting the survival and development of tumor cells and through which they interact and co-evolve with other tumor cells. In recent years, there has been a renewed interest in glycolysis and the TME. Many studies have found that glycolysis promotes tumor growth, metastasis, and chemoresistance, as well as inhibiting the apoptosis of tumor cells. In addition, lactic acid, a metabolite of glycolysis, can also accumulate in the TME, leading to reduced extracellular pH and immunosuppression, and affecting the TME. This review discusses the significance of glycolysis in tumor development, its association with the TME, and potential glycolysis-targeted therapies, to provide new ideas for the clinical treatment of tumors.

Keywords: glycolysis; immune cells; inflammatory factors; targeted therap; tumor microenvironment.

FIGURE 1

One glucose molecule is broken down intracellularly to two pyruvate molecules, which can enter the mitochondrion to participate in the tricarboxylic acid (TCA) cycle under aerobic conditions or to produce lactate under anaerobic conditions. Tumor cells rely mainly on aerobic glycolysis for energy production, even under oxygen-sufficient conditions, with one glucose molecule entering the glycolytic pathway to produce two net ATP molecules. Glycolysis involves the production of many intermediate metabolites apart from ATP. These intermediate metabolites can participate in other biosynthetic pathways, for example, glucose-6-phosphate can enter the pentose phosphate pathway, fructose 6-phosphate can enter the hexosamine biosynthesis pathway, dihydroxyacetone phosphate can be converted to glycerol 3-phosphate, and glycerol 3-phosphate can be converted to serine, cysteine, and glycine, among others.

FIGURE 2

Major cellular components and mediators in the TME, including normal cells, cancer cells, immune cells (T cells, B cells, dendritic cells, TAMs, and macrophages), cytokines, and extracellular matrix.

FIGURE 3

Major rate-limiting enzymes, metabolic enzymes, and transporters in the glycolytic pathway. PKM2, a key glycolytic enzyme regulated by fibronectin 1 (FN-1) secreted by hepatocellular carcinoma cells, controls PD-L1 expression in macrophages in a HIF-1α-dependent manner.