Reprogrammed metabolism is a hallmark of cancer. However, the metabolic dependency of cancer, from tumour initiation through disease progression and therapy resistance, requires a spectrum of distinct reprogrammed cellular metabolic pathways. These pathways include aerobic glycolysis, oxidative phosphorylation, reactive oxygen species generation, de novo lipid synthesis, fatty acid β-oxidation, amino acid (notably glutamine) metabolism and mitochondrial metabolism. This Review highlights the central roles of signal transducer and activator of transcription (STAT) proteins, notably STAT3, STAT5, STAT6 and STAT1, in orchestrating the highly dynamic metabolism not only of cancer cells but also of immune cells and adipocytes in the tumour microenvironment. STAT proteins are able to shape distinct metabolic processes that regulate tumour progression and therapy resistance by transducing signals from metabolites, cytokines, growth factors and their receptors; defining genetic programmes that regulate a wide range of molecules involved in orchestration of metabolism in cancer and immune cells; and regulating mitochondrial activity at multiple levels, including energy metabolism and lipid-mediated mitochondrial integrity. Given the central role of STAT proteins in regulation of metabolic states, they are potential therapeutic targets for altering metabolic reprogramming in cancer.
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H.Y. and C.Z. acknowledge funding from National Institutes of Health National Cancer Institute, USA (R01CA247368 and P30CA033572 to H.Y.; R21CA241283 to C.Z.).
The authors declare no competing interests.
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White and brown fat-storing cells. In the tumour microenvironment, adipocytes transfer lipids and/or fatty acids to nearby cancer cells, thereby promoting fatty acid oxidation and leading to cancer progression and chemoresistance.
A metabolic process that breaks down large molecules (lipids, proteins and nucleic acids) into smaller units (fatty acids, amino acids and nucleotides) that can be oxidized to produce energy or used for de novo biogenesis.
- CD8+ T cells
Cytotoxic effector cells that recognize specific antigens on cancer cells, as well as viral and bacterial antigens, and are powerful producers of the antitumour and antimicrobial cytokines (including tumour necrosis factor, granzyme B and interferon-γ (IFNγ)) necessary for antitumour immune responses.
- Fatty acid β-oxidation
(FAO). A multistep catabolic process that converts fatty acids to acetyl coenzyme A, which is further oxidized by the tricarboxylic acid cycle and electron transport chain to produce ATP; FAO is often increased in malignant cells, therapy-resistant cancer cells and immunosuppressive immune cells.
The process that converts glucose into pyruvic acid, which can be further catabolized to produce ATP through the tricarboxylic acid cycle.
- Myeloid-derived suppressor cells
(MDSCs). Diverse myeloid-lineage cells with an essential role in regulating innate and adaptive immunity. In cancer, activated MDSCs potently suppress cytotoxic immune cell function and promote metastasis by forming pre-metastatic niches and producing growth factors and other cancer-promoting molecules.
- Natural killer (NK) cells
Cytotoxic lymphocytes of the innate immune system with potent effects against tumour cells and virus-infected cells that are also involved in controlling tumour growth and metastasis.
- Nicotinamide adenine dinucleotide
A coenzyme involved in redox reactions in different metabolic pathways, including glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation; elevated nicotinamide adenine dinucleotide levels enhance glycolysis and promote increased proliferation and survival of cancer cells.
- Oxidative phosphorylation
A process that mainly occurs in mitochondria and is the metabolic pathway through which oxidation of nutrients releases chemical energy for ATP generation; this pathway releases more energy than anaerobic glycolysis.
- Pyruvate kinase M2
(PKM2). A member of the pyruvate kinase family that converts phosphoenolpyruvate to pyruvate, the final and rate-limiting step of glycolysis.
- Reactive oxygen species
(ROS). Highly reactive oxygen-containing free radicals; their accumulation promotes tumour cell growth, immune cell differentiation and/or immune cell activation, and causes damage to cellular components (including DNA and proteins) resulting in cell death.
- Regulatory T cells
(Treg cells). Also known as suppressor T cells, cells that suppress immune responses by downregulating the proliferation and cytotoxic function of effector T cells.
- Tumour-associated macrophages
(TAMs). Macrophages that produce immunosuppressive cytokines, chemokines, growth factors and metabolites that promote tumour cell growth and metastasis.
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Li, YJ., Zhang, C., Martincuks, A. et al. STAT proteins in cancer: orchestration of metabolism. Nat Rev Cancer 23, 115–134 (2023). https://doi.org/10.1038/s41568-022-00537-3
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