![]() ![]() In response, tumor cells increase their uptake Increased Arginine DependencyĬancers are characterized by a heightened metabolism and catabolism of the semi-essential amino acid arginine through the tissue-specific expression of arginase 1 (ARG1), arginase 2 (ARG2), or nitric oxide synthetase (iNOS) enzymes. This phenomenon is driven by the increased glycolytic rates of cancer cells, as the increased conversion of pyruvate to lactate limits the formation of acetyl-CoA needed to maintain the TCA cycle (Figure 1). Many cancers are characterized by enhanced glutamine metabolism and increased dependence on glutamine to fuel the tricarboxylic acid (TCA) cycle for the generation of building blocks for lipids, proteins, and nucleic acids (reviewed in ). Increased glycolysis in cancer cells leads to competition for the limited pool of glucose in the TME, depriving effector immune T cells, DCs, NK cells, and macrophages Tumor Glutamine Addiction The enhanced dependency on glycolysis is often mediated by overexpression or silencing of key enzymes in the glycolytic pathway (Figure 1). One salient metabolic change in cancers is an increased use of glucose and production of lactic acid via glycolysis, a process first described by Otto Warburg almost a century ago. ATP is then hydrolyzed to AMP by ectonucleotidase CD39 (canonical pathway) or by CD38 and CD203a (non-canonical pathway), and AMP Tumor Glucose Addiction and TME Acidification The proinflammatory adenosine precursor, ATP, is released from tumor cells into the TME through cell death or active ATP secretion induced by stress conditions such as hypoxia, nutrient deprivation, or inflammation. For instance, polyamines can diminish the expression Increased Extracellular Adenosine SignalingĮlevated extracellular adenosine levels in the TME promote tumor growth through well-established immunosuppressive effects (reviewed in ). Increased production and release of polyamines from tumor cells promote tumor progression in part by exerting suppressive effects on circulating and tumor-infiltrating leukocytes (Figures 1 and 2) (reviewed in ). Preclinical animal studies have demonstrated that increased biosynthesis of polyamines, small polycations that include putrescine, spermidine, and spermine, by cancer cells is important for cancer progression (reviewed in ). The immunosuppressive effect of tryptophan metabolism is likely mediated through Enhanced Polyamine Production The kynurenine pathway is the major route of tryptophan catabolism, with indoleamine 2,3-dioxygenase-1 (IDO1), indoleamine 2,3-dioxygenase-2 (IDO2), or tryptophan 2,3-dioxygenase (TDO2) regulating its first, rate-limiting step (Figure 1). Tryptophan metabolism promotes tumor progression by increasing the malignant properties of cancer cells and by suppressing antitumor immune responses (reviewed in ). Cancer immunotherapy, which involves the activation or enhancement of the patient’s immune system to eliminate tumor cells, has shown great promise in adult Heightened Tryptophan Metabolism Pediatric extracranial solid tumors mainly include neuroblastomas and sarcomas, with melanomas, retinoblastomas, and endocrine tumors making up a smaller proportion of cases. ![]() Solid malignancies in children comprise central nervous system (CNS) tumors, the leading cause of cancer-related deaths in children, and extracranial solid tumors. Section snippets Targeting Immunometabolism in Pediatric Solid Tumors
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