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Abnormal metabolism is a hallmark of cancer. The tumor microenvironment (TME) is often characteristic of nutrient competition, low pH, limited oxygen, and accumulation of metabolites. To sustain high proliferation rates, tumor cells must gain energy quickly by reprogramming metabolism. Reprogramming metabolism including glucose catabolism, amino acid synthesis and catabolism, lipid biogenesis, and other pathways within the cancer cells leads to profound changes both within cells and the TME. Warburg described aerobic glycolysis as a feature of cancer cells, named the Warburg effect. Glutamine consumption and metabolism can also be important characteristics of cancer cells. Although cancer cells and stromal cells can experience the same local environment concerning extracellular nutrients, these cells may have different metabolic demands. Symbiotic and competitive metabolic interactions between cell types have been reported in various cancers.
Fig.1 Features of the TME that contribute to metabolic heterogeneity. (Lyssiotis, 2017)
Abnormal metabolism of tumor cells causes metabolic changes in TME, such as hyperglycolysis, lactate and lipid accumulation, acidification, tryptophan deprivation. Tumor cells acquire and use different metabolites and reprogram their microenvironment to support tumor growth. In TME, tumor cells and stromal cells have different metabolic demands. During tumor progression and metastasis, these cells undergo rapid metabolic adaptations. The TME is a prime example of metabolic disorder in which cells surrounding the tumor can compromise or withstand the high metabolic demand of tumor cells by competing for nutrients or forming metabolic symbiosis. Symbiotic and competitive metabolic interactions between these cell types have been reported in various cancers.
Fig.2 Tumor-stroma metabolic communications in the TME. (Li, 2020)
The competition-caused deficiency of glucose, glutamine, fatty acids, and a couple of amino acids are known to affect the function of immune cells, including T cells, macrophages, dendritic cells, natural killer (NK) cells, and so on. both T cells and cancer cells can be highly glycolytic. Tumor cells by utilizing more glucose and glutamine create a state of nutrient deprivation for the T cells. This nutrient deprivation may result in T cells anergy, exhaustion, and death thereby compromising their effector functions. L-arginine, local depletion of tryptophan also results in T cell apoptosis and energy.
Tumors and other cells in the TME can also secrete immunosuppressive metabolites. Hypoxia, lactate, kynurenine, and other metabolic products cause immunosuppressive TME. For instance, glucose catabolism by cancer cells produces lactate to promote macrophage polarization into tumor-associated macrophages (TAMs) but inhibits NK cells and effector T cells. kynurenine facilitates Tregs differentiation but limits the function of effector T cells.
Hypoxic TME results in the metabolic symbiosis between hypoxic and normoxic compartments of the tumor. Symbiotic metabolic interactions have been suggested to occur between cancer-associated fibroblasts (CAFs), Tregs, myeloid-derived suppressor cells (MDSCs), and M2 TAMs. CAFs metabolize glucose through anaerobic glycolysis and export lactate, which is then taken up and utilized by oxidative cancer cells, known as the reverse Warburg effect. Citrulline captured by stromal adipocytes convert back to arginine and is utilized by cancer cells to form a symbiotic metabolic loop.
There is an extensive number of studies that have tried to target different metabolic pathways to improve TME and antitumor effects.
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