Cancer metabolism and tumor microenvironment: fostering each other?

Abels, E.R., Maas, S.L.N., Nieland, L., Wei, Z., Cheah, P.S., Tai, E., Kolsteeg, C.J., Dusoswa, S.A., Ting, D.T., Hickman, S., et al. (2019). Glioblastoma-associated microglia reprogramming is mediated by functional transfer of extracellular miR-21. Cell Rep 28, 3105–3119.e7.

Alam, N.A., Rowan, A.J., Wortham, N.C., Pollard, P.J., Mitchell, M., Tyrer, J.P., Barclay, E., Calonje, E., Manek, S., Adams, S.J., et al. (2003). Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 12, 1241–1252.

Allen, B.G., Bodeker, K.L., Smith, M.C., Monga, V., Sandhu, S., Hohl, R., Carlisle, T., Brown, H., Hollenbeck, N., Vollstedt, S., et al. (2019). First-in-human phase I clinical trial of pharmacologic ascorbate combined with radiation and temozolomide for newly diagnosed glioblastoma. Clin Cancer Res 25, 6590–6597.

Allis, C.D., and Jenuwein, T. (2016). The molecular hallmarks of epigenetic control. Nat Rev Genet 17, 487–500.

Anastasiou, D., Poulogiannis, G., Asara, J.M., Boxer, M.B., Jiang, J., Shen, M., Bellinger, G., Sasaki, A.T., Locasale, J.W., Auld, D.S., et al. (2011). Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334, 1278–1283.

Angelin, A., Gil-de-Gómez, L., Dahiya, S., Jiao, J., Guo, L., Levine, M.H., Wang, Z., Quinn Iii, W.J., Kopinski, P.K., Wang, L., et al. (2017). Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25, 1282–1293.e7.

Antonioli, L., Blandizzi, C., Pacher, P., and Haskó, G. (2013). Immunity, inflammation and cancer: a leading role for adenosine. Nat Rev Cancer 13, 842–857.

Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., Liu, H., Cross, J.R., Pfeffer, K., Coffer, P.J., et al. (2013). Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455.

Assaily, W., Rubinger, D.A., Wheaton, K., Lin, Y., Ma, W., Xuan, W., Brown-Endres, L., Tsuchihara, K., Mak, T.W., and Benchimol, S. (2011). ROS-mediated p53 induction of Lpin1 regulates fatty acid oxidation in response to nutritional stress. Mol Cell 44, 491–501.

Au Yeung, C.L., Co, N.N., Tsuruga, T., Yeung, T.L., Kwan, S.Y., Leung, C. S., Li, Y., Lu, E.S., Kwan, K., Wong, K.K., et al. (2016). Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun 7, 11150.

Balmer, M.L., Ma, E.H., Bantug, G.R., Grählert, J., Pfister, S., Glatter, T., Jauch, A., Dimeloe, S., Slack, E., Dehio, P., et al. (2016). Memory CD8+ T cells require increased concentrations of acetate induced by stress for optimal function. Immunity 44, 1312–1324.

Bao, Q., Gong, L., Wang, J., Wen, J., Shen, Y., and Zhang, W. (2018). Extracellular vesicle RNA sequencing reveals dramatic transcriptomic alterations between metastatic and primary osteosarcoma in a liquid biopsy approach. Ann Surg Oncol 25, 2642–2651.

Bar-Peled, L., and Sabatini, D.M. (2014). Regulation of mTORC1 by amino acids. Trends Cell Biol 24, 400–406.

Baratelli, F., Lin, Y., Zhu, L., Yang, S.C., Heuzé-Vourc’h, N., Zeng, G., Reckamp, K., Dohadwala, M., Sharma, S., and Dubinett, S.M. (2005). Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 175, 1483–1490.

Baroni, S., Romero-Cordoba, S., Plantamura, I., Dugo, M., D’Ippolito, E., Cataldo, A., Cosentino, G., Angeloni, V., Rossini, A., Daidone, M.G., et al. (2016). Exosome-mediated delivery of miR-9 induces cancer-associated fibroblast-like properties in human breast fibroblasts. Cell Death Dis 7, e2312.

Barthel, A., Okino, S.T., Liao, J., Nakatani, K., Li, J., Whitlock Jr., J.P., and Roth, R.A. (1999). Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem 274, 20281–20286.

Bates, G.J., Fox, S.B., Han, C., Leek, R.D., Garcia, J.F., Harris, A.L., and Banham, A.H. (2006). Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24, 5373–5380.

Becker, A., Thakur, B.K., Weiss, J.M., Kim, H.S., Peinado, H., and Lyden, D. (2016). Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell 30, 836–848.

Becker, L.M., O’Connell, J.T., Vo, A.P., Cain, M.P., Tampe, D., Bizarro, L., Sugimoto, H., McGow, A.K., Asara, J.M., Lovisa, S., et al. (2020). Epigenetic reprogramming of cancer-associated fibroblasts deregulates glucose metabolism and facilitates progression of breast cancer. Cell Rep 31, 107701.

Bengsch, B., Johnson, A.L., Kurachi, M., Odorizzi, P.M., Pauken, K.E., Attanasio, J., Stelekati, E., McLane, L.M., Paley, M.A., Delgoffe, G.M., et al. (2016). Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45, 358–373.

Bensaad, K., Tsuruta, A., Selak, M.A., Vidal, M.N.C., Nakano, K., Bartrons, R., Gottlieb, E., and Vousden, K.H. (2006). TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120.

Berod, L., Friedrich, C., Nandan, A., Freitag, J., Hagemann, S., Harmrolfs, K., Sandouk, A., Hesse, C., Castro, C.N., Bähre, H., et al. (2014). De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20, 1327–1333.

Bian, Y., Li, W., Kremer, D.M., Sajjakulnukit, P., Li, S., Crespo, J., Nwosu, Z.C., Zhang, L., Czerwonka, A., Pawłowska, A., et al. (2020). Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 585, 277–282.

Biffi, G., Oni, T.E., Spielman, B., Hao, Y., Elyada, E., Park, Y., Preall, J., and Tuveson, D.A. (2019). IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov 9, 282–301.

Boidot, R., Végran, F., Meulle, A., Le Breton, A., Dessy, C., Sonveaux, P., Lizard-Nacol, S., and Feron, O. (2012). Regulation of monocarboxylate transporter MCT1 expression by p53 mediates inward and outward lactate fluxes in tumors. Cancer Res 72, 939–948.

Bonuccelli, G., Whitaker-Menezes, D., Castello-Cros, R., Pavlides, S., Pestell, R.G., Fatatis, A., Witkiewicz, A.K., Vander Heiden, M.G., Migneco, G., Chiavarina, B., et al. (2010). The reverse Warburg effect: glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts. Cell Cycle 9, 1960–1971.

Boya, P., Reggiori, F., and Codogno, P. (2013). Emerging regulation and functions of autophagy. Nat Cell Biol 15, 713–720.

Brand, A., Singer, K., Koehl, G.E., Kolitzus, M., Schoenhammer, G., Thiel, A., Matos, C., Bruss, C., Klobuch, S., Peter, K., et al. (2016). LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 24, 657–671.

Brennen, W.N., Isaacs, J.T., and Denmeade, S.R. (2012a). Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther 11, 257–266.

Brennen, W.N., Rosen, D.M., Wang, H., Isaacs, J.T., and Denmeade, S.R. (2012b). Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J Natl Cancer Inst 104, 1320–1334.

Bronte, V., and Zanovello, P. (2005). Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5, 641–654.

Brown, T.P., and Ganapathy, V. (2020). Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther 206, 107451.

Buzek, J., Latonen, L., Kurki, S., Peltonen, K., and Laiho, M. (2002). Redox state of tumor suppressor p53 regulates its sequence-specific DNA binding in DNA-damaged cells by cysteine 277. Nucleic Acids Res 30, 2340–2348.

Calcinotto, A., Filipazzi, P., Grioni, M., Iero, M., De Milito, A., Ricupito, A., Cova, A., Canese, R., Jachetti, E., Rossetti, M., et al. (2012). Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res 72, 2746–2756.

Calvo, F., Ege, N., Grande-Garcia, A., Hooper, S., Jenkins, R.P., Chaudhry, S.I., Harrington, K., Williamson, P., Moeendarbary, E., Charras, G., et al. (2013). Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol 15, 637–646.

Carmona-Fontaine, C., Bucci, V., Akkari, L., Deforet, M., Joyce, J.A., and Xavier, J.B. (2013). Emergence of spatial structure in the tumor microenvironment due to the Warburg effect. Proc Natl Acad Sci USA 110, 19402–19407.

Carr, E.L., Kelman, A., Wu, G.S., Gopaul, R., Senkevitch, E., Aghvanyan, A., Turay, A.M., and Frauwirth, K.A. (2010). Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol 185, 1037–1044.

Cavalli, L.R., Varella-Garcia, M., and Liang, B.C. (1997). Diminished tumorigenic phenotype after depletion of mitochondrial DNA. Cell Growth Differ 8, 1189–1198.

Cavuoto, P., and Fenech, M.F. (2012). A review of methionine dependency and the role of methionine restriction in cancer growth control and lifespan extension. Cancer Treat Rev 38, 726–736.

Chang, C.H., Curtis, J.D., Maggi Jr., L.B., Faubert, B., Villarino, A.V., O’Sullivan, D., Huang, S.C.C., van der Windt, G.J.W., Blagih, J., Qiu, J., et al. (2013). Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251.

Chang, C.H., Qiu, J., O’Sullivan, D., Buck, M.D., Noguchi, T., Curtis, J.D., Chen, Q., Gindin, M., Gubin, M.M., van der Windt, G.J.W., et al. (2015). Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241.

Chang, T.Y., Chang, C.C.Y., Ohgami, N., and Yamauchi, Y. (2006). Cholesterol sensing, trafficking, and esterification. Annu Rev Cell Dev Biol 22, 129–157.

Chen, J.Y., Xu, L.F., Hu, H.L., Wen, Y.Q., Chen, D., and Liu, W.H. (2020a). miRNA-215–5p alleviates the metastasis of prostate cancer by targeting PGK1. Eur Rev Med Pharmacol Sci 24, 639–646.

Chen, P., Zuo, H., Xiong, H., Kolar, M.J., Chu, Q., Saghatelian, A., Siegwart, D.J., and Wan, Y. (2017). Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis. Proc Natl Acad Sci USA 114, 580–585.

Chen, R., Xu, M., Hogg, R.T., Li, J., Little, B., Gerard, R.D., and Garcia, J. A. (2012). The acetylase/deacetylase couple CREB-binding protein/Sirtuin 1 controls hypoxia-inducible factor 2 signaling. J Biol Chem 287, 30800–30811.

Chen, W., Quan, Y., Fan, S., Wang, H., Liang, J., Huang, L., Chen, L., Liu, Q., He, P., and Ye, Y. (2020b). Exosome-transmitted circular RNA hsa_circ_0051443 suppresses hepatocellular carcinoma progression. Cancer Lett 475, 119–128.

Chen, X., Wang, Z., Tong, F., Dong, X., Wu, G., and Zhang, R. (2020c). lncRNA UCA1 promotes gefitinib resistance as a ceRNA to target FOSL2 by sponging miR-143 in non-small cell lung cancer. Mol Ther Nucleic Acids 19, 643–653.

Chi, H. (2012). Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 12, 325–338.

Chiang, E.P.I., Wang, Y.C., Chen, W.W., and Tang, F.Y. (2009). Effects of insulin and glucose on cellular metabolic fluxes in homocysteine transsulfuration, remethylation, S-adenosylmethionine synthesis, and global deoxyribonucleic acid methylation. J Clin Endocrinol Metab 94, 1017–1025.

Choi, B.K., Lee, D.Y., Lee, D.G., Kim, Y.H., Kim, S.H., Oh, H.S., Han, C., and Kwon, B.S. (2017). 4–1BB signaling activates glucose and fatty acid metabolism to enhance CD8+ T cell proliferation. Cell Mol Immunol 14, 748–757.

Chowdhury, P.S., Chamoto, K., Kumar, A., and Honjo, T. (2018). PPAR-induced fatty acid oxidation in T cells increases the number of tumor-reactive CD8+ T cells and facilitates anti-PD-1 therapy. Cancer Immunol Res 6, 1375–1387.

Chowdhury, R., Yeoh, K.K., Tian, Y.M., Hillringhaus, L., Bagg, E.A., Rose, N.R., Leung, I.K.H., Li, X.S., Woon, E.C.Y., Yang, M., et al. (2011). The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep 12, 463–469.

Clambey, E.T., McNamee, E.N., Westrich, J.A., Glover, L.E., Campbell, E. L., Jedlicka, P., de Zoeten, E.F., Cambier, J.C., Stenmark, K.R., Colgan, S.P., et al. (2012). Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci USA 109, E2784–E2793.

Colegio, O.R., Chu, N.Q., Szabo, A.L., Chu, T., Rhebergen, A.M., Jairam, V., Cyrus, N., Brokowski, C.E., Eisenbarth, S.C., Phillips, G.M., et al. (2014). Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563.

Commisso, C., Davidson, S.M., Soydaner-Azeloglu, R.G., Parker, S.J., Kamphorst, J.J., Hackett, S., Grabocka, E., Nofal, M., Drebin, J.A., Thompson, C.B., et al. (2013). Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637.

Constant, J.S., Feng, J.J., Zabel, D.D., Yuan, H., Suh, D.Y., Scheuenstuhl, H., Hunt, T.K., and Hussain, M.Z. (2000). Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia. Wound Repair Regen 8, 353–360.

Corcoran, R.B., and Scott, M.P. (2006). Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci USA 103, 8408–8413.

Costa, A., Kieffer, Y., Scholer-Dahirel, A., Pelon, F., Bourachot, B., Cardon, M., Sirven, P., Magagna, I., Fuhrmann, L., Bernard, C., et al. (2018). Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479.e10.

Coutzac, C., Jouniaux, J.M., Paci, A., Schmidt, J., Mallardo, D., Seck, A., Asvatourian, V., Cassard, L., Saulnier, P., Lacroix, L., et al. (2020). Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat Commun 11, 2168.

Cubillos-Ruiz, J.R., Silberman, P.C., Rutkowski, M.R., Chopra, S., Perales-Puchalt, A., Song, M., Zhang, S., Bettigole, S.E., Gupta, D., Holcomb, K., et al. (2015). ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161, 1527–1538.

Curiel, T.J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J.R., Zhang, L., Burow, M., et al. (2004). Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10, 942–949.

Curtis, M., Kenny, H.A., Ashcroft, B., Mukherjee, A., Johnson, A., Zhang, Y., Helou, Y., Batlle, R., Liu, X., Gutierrez, N., et al. (2019). Fibroblasts mobilize tumor cell glycogen to promote proliferation and metastasis. Cell Metab 29, 141–155.e9.

D’Asti, E., Huang, A., Kool, M., Meehan, B., Chan, J.A., Jabado, N., Korshunov, A., Pfister, S.M., and Rak, J. (2016). Tissue factor regulation by miR-520g in primitive neuronal brain tumor cells. Am J Pathol 186, 446–459.

Dai, X., Chen, C., Yang, Q., Xue, J., Chen, X., Sun, B., Luo, F., Liu, X., Xiao, T., Xu, H., et al. (2018). Exosomal circRNA_100284 from arsenite-transformed cells, via microRNA-217 regulation of EZH2, is involved in the malignant transformation of human hepatic cells by accelerating the cell cycle and promoting cell proliferation. Cell Death Dis 9, 454.

Dang, L., White, D.W., Gross, S., Bennett, B.D., Bittinger, M.A., Driggers, E.M., Fantin, V.R., Jang, H.G., Jin, S., Keenan, M.C., et al. (2010). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 465, 966.

Dannenberg, A.J., and Subbaramaiah, K. (2003). Targeting cyclooxygenase-2 in human neoplasia. Cancer Cell 4, 431–436.

Dansen, T.B., Smits, L.M.M., van Triest, M.H., de Keizer, P.L.J., van Leenen, D., Koerkamp, M.G., Szypowska, A., Meppelink, A., Brenkman, A.B., Yodoi, J., et al. (2009). Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nat Chem Biol 5, 664–672.

De Veirman, K., Wang, J., Xu, S., Leleu, X., Himpe, E., Maes, K., De Bruyne, E., Van Valckenborgh, E., Vanderkerken, K., Menu, E., et al. (2016). Induction of miR-146a by multiple myeloma cells in mesenchymal stromal cells stimulates their pro-tumoral activity. Cancer Lett 377, 17–24.

Delgoffe, G.M., Kole, T.P., Zheng, Y., Zarek, P.E., Matthews, K.L., Xiao, B., Worley, P.F., Kozma, S.C., and Powell, J.D. (2009). The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844.

Deng, L., Yao, P., Li, L., Ji, F., Zhao, S., Xu, C., Lan, X., and Jiang, P. (2020). p53-mediated control of aspartate-asparagine homeostasis dictates LKB1 activity and modulates cell survival. Nat Commun 11, 1755.

Deng, M., Yuan, H., Liu, S., Hu, Z., and Xiao, H. (2019). Exosome-transmitted LINC00461 promotes multiple myeloma cell proliferation and suppresses apoptosis by modulating microRNA/BCL-2 expression. Cytotherapy 21, 96–106.

Deprez, J., Vertommen, D., Alessi, D.R., Hue, L., and Rider, M.H. (1997). Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J Biol Chem 272, 17269–17275.

Di Modica, M., Regondi, V., Sandri, M., Iorio, M.V., Zanetti, A., Tagliabue, E., Casalini, P., and Triulzi, T. (2017). Breast cancer-secreted miR-939 downregulates VE-cadherin and destroys the barrier function of endothelial monolayers. Cancer Lett 384, 94–100.

Dong, W., Li, H., and Wu, X. (2019). Rab11-FIP2 suppressed tumor growth via regulation of PGK1 ubiquitination in non-small cell lung cancer. Biochem Biophys Res Commun 508, 60–65.

Dong, Y., Tu, R., Liu, H., and Qing, G. (2020). Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat. Sig Transduct Target Ther 5, 124.

Dror, S., Sander, L., Schwartz, H., Sheinboim, D., Barzilai, A., Dishon, Y., Apcher, S., Golan, T., Greenberger, S., Barshack, I., et al. (2016). Melanoma miRNA trafficking controls tumour primary niche formation. Nat Cell Biol 18, 1006–1017.

Du, W., Jiang, P., Mancuso, A., Stonestrom, A., Brewer, M.D., Minn, A.J., Mak, T.W., Wu, M., and Yang, X. (2013). TAp73 enhances the pentose phosphate pathway and supports cell proliferation. Nat Cell Biol 15, 991–1000.

Duscha, A., Gisevius, B., Hirschberg, S., Yissachar, N., Stangl, G.I., Eilers, E., Bader, V., Haase, S., Kaisler, J., David, C., et al. (2020). Propionic acid shapes the multiple sclerosis disease course by an immunomodulatory mechanism. Cell 180, 1067–1080.e16.

Düvel, K., Yecies, J.L., Menon, S., Raman, P., Lipovsky, A.I., Souza, A.L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al. (2010). Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39, 171–183.

Dvorak, T.M., and Catalano, A.E. (2016). Exclusion of introduced deer increases size and seed production success in an island-endemic plant species. Ecol Evol 6, 544–551.

Eagle, H. (1955). The minimum vitamin requirements of the L and HeLa cells in tissue culture, the production of specific vitamin deficiencies, and their cure. J Exp Med 102, 595–600.

Eaton, S. (2008). Multiple roles for lipids in the Hedgehog signalling pathway. Nat Rev Mol Cell Biol 9, 437–445.

Eberhardy, S.R., and Farnham, P.J. (2001). c-Myc mediates activation of the cad promoter via a post-RNA polymerase II recruitment mechanism. J Biol Chem 276, 48562–48571.

Facciabene, A., Peng, X., Hagemann, I.S., Balint, K., Barchetti, A., Wang, L.P., Gimotty, P.A., Gilks, C.B., Lal, P., Zhang, L., et al. (2011). Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230.

Fan, J., Ye, J., Kamphorst, J.J., Shlomi, T., Thompson, C.B., and Rabinowitz, J.D. (2014). Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510, 298–302.

Fang, J.H., Zhang, Z.J., Shang, L.R., Luo, Y.W., Lin, Y.F., Yuan, Y., and Zhuang, S.M. (2018a). Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins. Hepatology 68, 1459–1475.

Fang, T., Lv, H., Lv, G., Li, T., Wang, C., Han, Q., Yu, L., Su, B., Guo, L., Huang, S., et al. (2018b). Tumor-derived exosomal miR-1247–3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun 9, 191.

Fantin, V.R., St-Pierre, J., and Leder, P. (2006). Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 10, 172.

Faubert, B., Li, K.Y., Cai, L., Hensley, C.T., Kim, J., Zacharias, L.G., Yang, C., Do, Q.N., Doucette, S., Burguete, D., et al. (2017). Lactate metabolism in human lung tumors. Cell 171, 358–371.e9.

Feng, J., Yang, H., Zhang, Y., Wei, H., Zhu, Z., Zhu, B., Yang, M., Cao, W., Wang, L., and Wu, Z. (2017). Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene 36, 5829–5839.

Field, C.S., Baixauli, F., Kyle, R.L., Puleston, D.J., Cameron, A.M., Sanin, D.E., Hippen, K.L., Loschi, M., Thangavelu, G., Corrado, M., et al. (2020). Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg suppressive function. Cell Metab 31, 422–437.e5.

Figueroa, M.E., Abdel-Wahab, O., Lu, C., Ward, P.S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H.F., et al. (2010). Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567.

Finlay, D.K., Rosenzweig, E., Sinclair, L.V., Feijoo-Carnero, C., Hukelmann, J.L., Rolf, J., Panteleyev, A.A., Okkenhaug, K., and Cantrell, D.A. (2012). PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med 209, 2441–2453.

Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., et al. (2007). Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819.

Fletcher, M., Ramirez, M.E., Sierra, R.A., Raber, P., Thevenot, P., Al-Khami, A.A., Sanchez-Pino, D., Hernandez, C., Wyczechowska, D.D., Ochoa, A.C., et al. (2015). L-arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res 75, 275–283.

Fong, M.Y., Zhou, W., Liu, L., Alontaga, A.Y., Chandra, M., Ashby, J., Chow, A., O’Connor, S.T.F., Li, S., Chin, A.R., et al. (2015). Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol 17, 183–194.

Fourquet, S., Guerois, R., Biard, D., and Toledano, M.B. (2010). Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation. J Biol Chem 285, 8463–8471.

Frauwirth, K.A., Riley, J.L., Harris, M.H., Parry, R.V., Rathmell, J.C., Plas, D.R., Elstrom, R.L., June, C.H., and Thompson, C.B. (2002). The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769–777.

Frericks, M., Burgoon, L.D., Zacharewski, T.R., and Esser, C. (2008). Promoter analysis of TCDD-inducible genes in a thymic epithelial cell line indicates the potential for cell-specific transcription factor crosstalk in the AhR response. Toxicol Appl Pharmacol 232, 268–279.

Friese, M.A., Wischhusen, J., Wick, W., Weiler, M., Eisele, G., Steinle, A., and Weller, M. (2004). RNA interference targeting transforming growth factor-β enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res 64, 7596–7603.

Gagnon, E., Schubert, D.A., Gordo, S., Chu, H.H., and Wucherpfennig, K. W. (2012). Local changes in lipid environment of TCR microclusters regulate membrane binding by the CD3ε cytoplasmic domain. J Exp Med 209, 2423–2439.

Gamcsik, M.P., Kasibhatla, M.S., Teeter, S.D., and Colvin, O.M. (2012). Glutathione levels in human tumors. Biomarkers 17, 671–691.

Gao, P., Tchernyshyov, I., Chang, T.C., Lee, Y.S., Kita, K., Ochi, T., Zeller, K.I., De Marzo, A.M., Van Eyk, J.E., Mendell, J.T., et al. (2009). c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765.

Gao, X., Sanderson, S.M., Dai, Z., Reid, M.A., Cooper, D.E., Lu, M., Richie Jr, J.P., Ciccarella, A., Calcagnotto, A., Mikhael, P.G., et al. (2019). Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 572, 397–401.

Garin-Chesa, P., Old, L.J., and Rettig, W.J. (1990). Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA 87, 7235–7239.

Geiger, R., Rieckmann, J.C., Wolf, T., Basso, C., Feng, Y., Fuhrer, T., Kogadeeva, M., Picotti, P., Meissner, F., Mann, M., et al. (2016). L-arginine modulates T cell metabolism and enhances survival and antitumor activity. Cell 167, 829–842.e13.

Geltink, R.I.K., Kyle, R.L., and Pearce, E.L. (2018). Unraveling the complex interplay between T cell metabolism and function. Annu Rev Immunol 36, 461–488.

Gerriets, V.A., Kishton, R.J., Johnson, M.O., Cohen, S., Siska, P.J., Nichols, A.G., Warmoes, M.O., de Cubas, A.A., MacIver, N.J., Locasale, J.W., et al. (2016). Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat Immunol 17, 1459–1466.

Gerriets, V.A., and Rathmell, J.C. (2012). Metabolic pathways in T cell fate and function. Trends Immunol 33, 168–173.

Glatz, J.F.C., Luiken, J.J.F.P., and Bonen, A. (2010). Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. Physiol Rev 90, 367–417.

Göbl, C., Morris, V.K., van Dam, L., Visscher, M., Polderman, P.E., Hartlmüller, C., de Ruiter, H., Hora, M., Liesinger, L., Birner-Gruenberger, R., et al. (2020). Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A. Redox Biol 28, 101316.

Gomes, A.P., Ilter, D., Low, V., Endress, J.E., Fernández-García, J., Rosenzweig, A., Schild, T., Broekaert, D., Ahmed, A., Planque, M., et al. (2020). Age-induced accumulation of methylmalonic acid promotes tumour progression. Nature 585, 283–287.

Gordan, J.D., Thompson, C.B., and Simon, M.C. (2007). HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12, 108–113.

Gorrini, C., Harris, I.S., and Mak, T.W. (2013). Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12, 931–947.

Gottfried, E., Kunz-Schughart, L.A., Ebner, S., Mueller-Klieser, W., Hoves, S., Andreesen, R., Mackensen, A., and Kreutz, M. (2006). Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107, 2013–2021.

Gottlob, K., Majewski, N., Kennedy, S., Kandel, E., Robey, R.B., and Hay, N. (2001). Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 15, 1406–1418.

Gouge, J., Satia, K., Guthertz, N., Widya, M., Thompson, A.J., Cousin, P., Dergai, O., Hernandez, N., and Vannini, A. (2015). Redox signaling by the RNA polymerase III TFIIB-related factor Brf2. Cell 163, 1375–1387.

Grek, C.L., and Tew, K.D. (2010). Redox metabolism and malignancy. Curr Opin Pharmacol 10, 362–368.

Gubser, P.M., Bantug, G.R., Razik, L., Fischer, M., Dimeloe, S., Hoenger, G., Durovic, B., Jauch, A., and Hess, C. (2013). Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat Immunol 14, 1064–1072.

Gut, P., and Verdin, E. (2013). The nexus of chromatin regulation and intermediary metabolism. Nature 502, 489–498.

Hanahan, D., and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646–674.

Hardie, D.G. (2007). AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8, 774–785.

Harvey, M., McArthur, M.J., Montgomery Jr., C.A., Butel, J.S., Bradley, A., and Donehower, L.A. (1993). Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat Genet 5, 225–229.

Hawkins, C.L., and Davies, M.J. (2019). Detection, identification, and quantification of oxidative protein modifications. J Biol Chem 294, 19683–19708.

Haxhinasto, S., Mathis, D., and Benoist, C. (2008). The AKT-mTOR axis regulates de novo differentiation of CD4+ Foxp3+ cells. J Exp Med 205, 565–574.

Hayes, J.D., Dinkova-Kostova, A.T., and Tew, K.D. (2020). Oxidative stress in cancer. Cancer Cell 38, 167–197.

He, W., Miao, F.J.P., Lin, D.C.H., Schwandner, R.T., Wang, Z., Gao, J., Chen, J.L., Tian, H., and Ling, L. (2004). Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429, 188–193.

Hensley, C.T., Faubert, B., Yuan, Q., Lev-Cohain, N., Jin, E., Kim, J., Jiang, L., Ko, B., Skelton, R., Loudat, L., et al. (2016). Metabolic heterogeneity in human lung tumors. Cell 164, 681–694.

Herzig, S., and Shaw, R.J. (2018). AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19, 121–135.

Hino, S., Sakamoto, A., Nagaoka, K., Anan, K., Wang, Y., Mimasu, S., Umehara, T., Yokoyama, S., Kosai, K.I., and Nakao, M. (2012). FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. Nat Commun 3, 758.

Hirata, E., Girotti, M.R., Viros, A., Hooper, S., Spencer-Dene, B., Matsuda, M., Larkin, J., Marais, R., and Sahai, E. (2015). Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell 27, 574–588.

Hlavatá, L., Aguilaniu, H., Pichová, A., and Nyström, T. (2003). The oncogenic RAS2(val19) mutation locks respiration, independently of PKA, in a mode prone to generate ROS. EMBO J 22, 3337–3345.

Ho, P.C., Bihuniak, J.D., Macintyre, A.N., Staron, M., Liu, X., Amezquita, R., Tsui, Y.C., Cui, G., Micevic, G., Perales, J.C., et al. (2015). Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228.

Hörig, H., Spagnoli, G.C., Filgueira, L., Babst, R., Gallati, H., Harder, F., Juretic, A., and Heberer, M. (1993). Exogenous glutamine requirement is confined to late events of T cell activation. J Cell Biochem 53, 343–351.

Hsu, Y.L., Hung, J.Y., Chang, W.A., Jian, S.F., Lin, Y.S., Pan, Y.C., Wu, C. Y., and Kuo, P.L. (2018). Hypoxic lung-cancer-derived extracellular vesicle microRNA-103a increases the oncogenic effects of macrophages by targeting PTEN. Mol Ther 26, 568–581.

Hsu, Y.L., Huang, M.S., Hung, J.Y., Chang, W.A., Tsai, Y.M., Pan, Y.C., Lin, Y.S., Tsai, H.P., and Kuo, P.L. (2020). Bone-marrow-derived cell-released extracellular vesicle miR-92a regulates hepatic pre-metastatic niche in lung cancer. Oncogene 39, 739–753.

Hu, H., Zhu, W., Qin, J., Chen, M., Gong, L., Li, L., Liu, X., Tao, Y., Yin, H., Zhou, H., et al. (2017). Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis. Hepatology 65, 515–528.

Hu, W., Zhang, C., Wu, R., Sun, Y., Levine, A., and Feng, Z. (2010). Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA 107, 7455–7460.

Hu, Z., Qu, G., Yu, X., Jiang, H., Teng, X.L., Ding, L., Hu, Q., Guo, X., Zhou, Y., Wang, F., et al. (2019). Acylglycerol kinase maintains metabolic state and immune responses of CD8+ T cells. Cell Metab 30, 290–302.e5.

Huang, D., Li, T., Li, X., Zhang, L., Sun, L., He, X., Zhong, X., Jia, D., Song, L., Semenza, G.L., et al. (2014). HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep 8, 1930–1942.

Huang, B., Song, B.L., and Xu, C. (2020a). Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab 2, 132–141.

Huang, D., Li, T., Wang, L., Zhang, L., Yan, R., Li, K., Xing, S., Wu, G., Hu, L., Jia, W., et al. (2016). Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress. Cell Res 26, 1112–1130.

Huang, X.Y., Huang, Z.L., Huang, J., Xu, B., Huang, X.Y., Xu, Y.H., Zhou, J., and Tang, Z.Y. (2020b). Exosomal circRNA-100338 promotes hepatocellular carcinoma metastasis via enhancing invasiveness and angiogenesis. J Exp Clin Cancer Res 39, 20.

Huang, Y., Song, N., Ding, Y., Yuan, S., Li, X., Cai, H., Shi, H., and Luo, Y. (2009). Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res 69, 7529–7537.

Huber, V., Camisaschi, C., Berzi, A., Ferro, S., Lugini, L., Triulzi, T., Tuccitto, A., Tagliabue, E., Castelli, C., and Rivoltini, L. (2017). Cancer acidity: an ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol 43, 74–89.

Hui, S., Ghergurovich, J.M., Morscher, R.J., Jang, C., Teng, X., Lu, W., Esparza, L.A., Reya, T., Le Zhan, T., Yanxiang Guo, J., et al. (2017). Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118.

Humpton, T.J., and Vousden, K.H. (2016). Regulation of cellular metabolism and hypoxia by p53. Cold Spring Harb Perspect Med 6, a026146.

Isaacs, J.S., Jung, Y.J., Mole, D.R., Lee, S., Torres-Cabala, C., Chung, Y.L., Merino, M., Trepel, J., Zbar, B., Toro, J., et al. (2005). HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8, 143–153.

Jacks, T., Remington, L., Williams, B.O., Schmitt, E.M., Halachmi, S., Bronson, R.T., and Weinberg, R.A. (1994). Tumor spectrum analysis in p53-mutant mice. Curr Biol 4, 1–7.

Jarnicki, A.G., Lysaght, J., Todryk, S., and Mills, K.H.G. (2006). Suppression of antitumor immunity by IL-10 and TGF-β-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J Immunol 177, 896–904.

Jeanne, M., Lallemand-Breitenbach, V., Ferhi, O., Koken, M., Le Bras, M., Duffort, S., Peres, L., Berthier, C., Soilihi, H., Raught, B., et al. (2010). PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3. Cancer Cell 18, 88–98.

Jenuwein, T., and Allis, C.D. (2001). Translating the histone code. Science 293, 1074–1080.

Jiang, D., LaGory, E.L., Kenzelmann Brož, D., Bieging, K.T., Brady, C.A., Link, N., Abrams, J.M., Giaccia, A.J., and Attardi, L.D. (2015). Analysis of p53 transactivation domain mutants reveals Acad11 as a metabolic target important for p53 pro-survival function. Cell Rep 10, 1096–1109.

Jiang, M.J., Chen, Y.Y., Dai, J.J., Gu, D.N., Mei, Z., Liu, F.R., Huang, Q., and Tian, L. (2020). Dying tumor cell-derived exosomal miR-194–5p potentiates survival and repopulation of tumor repopulating cells upon radiotherapy in pancreatic cancer. Mol Cancer 19, 68.

Jiang, P., Du, W., Mancuso, A., Wellen, K.E., and Yang, X. (2013a). Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493, 689–693.

Jiang, P., Du, W., Wang, X., Mancuso, A., Gao, X., Wu, M., and Yang, X. (2011). p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 13, 310–316.

Jiang, P., Du, W., and Yang, X. (2013b). A critical role of glucose-6-phosphate dehydrogenase in TAp73-mediated cell proliferation. Cell Cycle 12, 3720–3726.

Kaelin, W.G. Jr., and McKnight, S.L. (2013). Influence of metabolism on epigenetics and disease. Cell 153, 56–69.

Kalluri, R. (2016). The biology and function of fibroblasts in cancer. Nat Rev Cancer 16, 582–598.

Kamphorst, J.J., Cross, J.R., Fan, J., de Stanchina, E., Mathew, R., White, E.P., Thompson, C.B., and Rabinowitz, J.D. (2013). Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci USA 110, 8882–8887.

Katada, S., Imhof, A., and Sassone-Corsi, P. (2012). Connecting threads: epigenetics and metabolism. Cell 148, 24–28.

Kelly, B., and Pearce, E.L. (2020). Amino assets: how amino acids support immunity. Cell Metab 32, 154–175.

Kidani, Y., Elsaesser, H., Hock, M.B., Vergnes, L., Williams, K.J., Argus, J. P., Marbois, B.N., Komisopoulou, E., Wilson, E.B., Osborne, T.F., et al. (2013). Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol 14, 489–499.

Kim, J.E., Roh, E., Lee, M.H., Yu, D.H., Kim, D.J., Lim, T.G., Jung, S.K., Peng, C., Cho, Y.Y., Dickinson, S., et al. (2016). Fyn is a redox sensor involved in solar ultraviolet light-induced signal transduction in skin carcinogenesis. Oncogene 35, 4091–4101.

King, A., Selak, M.A., and Gottlieb, E. (2006). Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25, 4675–4682

Kitajima, K., Nakajo, M., Kaida, H., Minamimoto, R., Hirata, K., Tsurusaki, M., Doi, H., Ueno, Y., Sofue, K., and Tamaki, Y. (2017). Present and future roles of FDG-PET/CT imaging in the management of gastrointestinal cancer: an update. Nagoya J Med Sci 79, 527–543.

Kiyozumi, Y., Baba, Y., Okadome, K., Yagi, T., Ishimoto, T., Iwatsuki, M., Miyamoto, Y., Yoshida, N., Watanabe, M., Komohara, Y., et al. (2019). IDO1 expression is associated with immune tolerance and poor prognosis in patients with surgically resected esophageal cancer. Ann Surg 269, 1101–1108.

Kondoh, H., Lleonart, M.E., Gil, J., Wang, J., Degan, P., Peters, G., Martinez, D., Carnero, A., and Beach, D. (2005). Glycolytic enzymes can modulate cellular life span. Cancer Res 65, 177–185.

Krajcovic, M., Krishna, S., Akkari, L., Joyce, J.A., and Overholtzer, M. (2013). mTOR regulates phagosome and entotic vacuole fission. Mol Biol Cell 24, 3736–3745.

Kraman, M., Bambrough, P.J., Arnold, J.N., Roberts, E.W., Magiera, L., Jones, J.O., Gopinathan, A., Tuveson, D.A., and Fearon, D.T. (2010). Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330, 827–830.

Kruiswijk, F., Labuschagne, C.F., and Vousden, K.H. (2015). p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol 16, 393–405.

Kumagai, S., Togashi, Y., Sakai, C., Kawazoe, A., Kawazu, M., Ueno, T., Sato, E., Kuwata, T., Kinoshita, T., Yamamoto, M., et al. (2020). An oncogenic alteration creates a microenvironment that promotes tumor progression by conferring a metabolic advantage to regulatory T cells. Immunity 53, 187–203.e8.

Kunkl, M., Sambucci, M., Ruggieri, S., Amormino, C., Tortorella, C., Gasperini, C., Battistini, L., and Tuosto, L. (2019). CD28 autonomous signaling up-regulates c-Myc expression and promotes glycolysis enabling inflammatory T cell responses in multiple sclerosis. Cells 8, 575.

Kurniawan, H., Franchina, D.G., Guerra, L., Bonetti, L., Baguet, L.S., Grusdat, M., Schlicker, L., Hunewald, O., Dostert, C., Merz, M.P., et al. (2020). Glutathione restricts serine metabolism to preserve regulatory T cell function. Cell Metab 31, 920–936.e7.

Lai, Z.W., Pineau, T., and Esser, C. (1996). Identification of dioxin-responsive elements (DREs) in the 5’ regions of putative dioxin-inducible genes. Chem Biol Interact 100, 97–112.

Lay, A.J., Jiang, X.M., Kisker, O., Flynn, E., Underwood, A., Condron, R., and Hogg, P.J. (2000). Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase. Nature 408, 869–873.

Le, M.T.N., Hamar, P., Guo, C., Basar, E., Perdigão-Henriques, R., Balaj, L., and Lieberman, J. (2014). miR-200-containing extracellular vesicles promote breast cancer cell metastasis. J Clin Invest 124, 5109–5128.

Lee, D.C., Sohn, H.A., Park, Z.Y., Oh, S., Kang, Y.K., Lee, K.M., Kang, M., Jang, Y.J., Yang, S.J., Hong, Y.K., et al. (2015). A lactate-induced response to hypoxia. Cell 161, 595–609.

Lee, G., Won, H.S., Lee, Y.M., Choi, J.W., Oh, T.I., Jang, J.H., Choi, D.K., Lim, B.O., Kim, Y.J., Park, J.W., et al. (2016). Oxidative dimerization of PHD2 is responsible for its inactivation and contributes to metabolic reprogramming via HIF-1α activation. Sci Rep 6, 18928.

Lee, I.K., Song, H., Kim, H., Kim, I.S., Tran, N.L., Kim, S.H., Oh, S.J., and Lee, J.M. (2020). RORα regulates cholesterol metabolism of CD8+ T cells for anticancer immunity. Cancers 12, 1733.

Lee, J.E., Walsh, M.C., Hoehn, K.L., James, D.E., Wherry, E.J., and Choi, Y. (2014a). Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J Immunol 192, 3190–3199.

Lee, J.V., Carrer, A., Shah, S., Snyder, N.W., Wei, S., Venneti, S., Worth, A. J., Yuan, Z.F., Lim, H.W., Liu, S., et al. (2014b). Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab 20, 306–319.

Leone, R.D., Zhao, L., Englert, J.M., Sun, I.M., Oh, M.H., Sun, I.H., Arwood, M.L., Bettencourt, I.A., Patel, C.H., Wen, J., et al. (2019). Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013–1021.

Letouzé, E., Martinelli, C., Loriot, C., Burnichon, N., Abermil, N., Ottolenghi, C., Janin, M., Menara, M., Nguyen, A.T., Benit, P., et al. (2013). SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752.

Li, B., Carey, M., and Workman, J.L. (2007). The role of chromatin during transcription. Cell 128, 707–719.

Li, B., Xu, H., Han, H., Song, S., Zhang, X., Ouyang, L., Qian, C., Hong, Y., Qiu, Y., Zhou, W., et al. (2018a). Exosome-mediated transfer of lncRUNX2-AS1 from multiple myeloma cells to MSCs contributes to osteogenesis. Oncogene 37, 5508–5519.

Li, F., He, X., Ye, D., Lin, Y., Yu, H., Yao, C., Huang, L., Zhang, J., Wang, F., Xu, S., et al. (2015). NADP+-IDH mutations promote hypersuccinylation that impairs mitochondria respiration and induces apoptosis resistance. Mol Cell 60, 661–675.

Li, H., Courtois, E.T., Sengupta, D., Tan, Y., Chen, K.H., Goh, J.J.L., Kong, S.L., Chua, C., Hon, L.K., Tan, W.S., et al. (2017). Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat Genet 49, 708–718.

Li, J., Li, Z., Jiang, P., Peng, M., Zhang, X., Chen, K., Liu, H., Bi, H., Liu, X., and Li, X. (2018b). Circular RNA IARS (circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis. J Exp Clin Cancer Res 37, 177.

Li, L., Li, C., Wang, S., Wang, Z., Jiang, J., Wang, W., Li, X., Chen, J., Liu, K., Li, C., et al. (2016a). Exosomes derived from hypoxic oral squamous cell carcinoma cells deliver miR-21 to normoxic cells to elicit a prometastatic phenotype. Cancer Res 76, 1770–1780.

Li, L., Li, L., Li, W., Chen, T., Bin Zou Zhao, L., Wang, H., Wang, X., Xu, L., Liu, X., Wang, D., et al. (2018c). TAp73-induced phosphofructokinase-1 transcription promotes the Warburg effect and enhances cell proliferation. Nat Commun 9, 4683.

Li, L., Liu, X., Sanders, K.L., Edwards, J.L., Ye, J., Si, F., Gao, A., Huang, L., Hsueh, E.C., Ford, D.A., et al. (2019a). TLR8-mediated metabolic control of human treg function: a mechanistic target for cancer immunotherapy. Cell Metab 29, 103–123.e5.

Li, L., Mao, Y., Zhao, L., Li, L., Wu, J., Zhao, M., Du, W., Yu, L., and Jiang, P. (2019b). p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis. Nature 567, 253–256.

Li, S.T., Huang, D., Shen, S., Cai, Y., Xing, S., Wu, G., Jiang, Z., Hao, Y., Yuan, M., Wang, N., et al. (2020). Myc-mediated SDHA acetylation triggers epigenetic regulation of gene expression and tumorigenesis. Nat Metab 2, 256–269.

Li, X., Jiang, Y., Meisenhelder, J., Yang, W., Hawke, D.H., Zheng, Y., Xia, Y., Aldape, K., He, J., Hunter, T., et al. (2016b). Mitochondria-translocated PGK1 functions as a protein kinase to coordinate glycolysis and the TCA cycle in tumorigenesis. Mol Cell 61, 705–719.

Li, X., Wenes, M., Romero, P., Huang, S.C.C., Fendt, S.M., and Ho, P.C. (2019c). Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat Rev Clin Oncol 16, 425–441.

Li, X., Zheng, Y., and Lu, Z. (2016c). PGK1 is a new member of the protein kinome. Cell Cycle 15, 1803–1804.

Li, X.X., Wang, Z.J., Zheng, Y., Guan, Y.F., Yang, P.B., Chen, X., Peng, C., He, J.P., Ai, Y.L., Wu, S.F., et al. (2018d). Nuclear receptor Nur77 facilitates melanoma cell survival under metabolic stress by protecting fatty acid oxidation. Mol Cell 69, 480–492.e7.

Li, Z., Niu, H., Qin, Q., Yang, S., Wang, Q., Yu, C., Wei, Z., Jin, Z., Wang, X., Yang, A., et al. (2019d). lncRNA UCA1 mediates resistance to cisplatin by regulating the miR-143/FOSL2-signaling pathway in ovarian cancer. Mol Ther Nucleic Acids 17, 92–101.

Li, Z., Qin, X., Bian, W., Li, Y., Shan, B., Yao, Z., and Li, S. (2019e). Exosomal lncRNA ZFAS1 regulates esophageal squamous cell carcinoma cell proliferation, invasion, migration and apoptosis via microRNA-124/STAT3 axis. J Exp Clin Cancer Res 38, 477.

Liang, C., Shi, S., Qin, Y., Meng, Q., Hua, J., Hu, Q., Ji, S., Zhang, B., Xu, J., and Yu, X.J. (2020). Localisation of PGK1 determines metabolic phenotype to balance metastasis and proliferation in patients with SMAD4-negative pancreatic cancer. Gut 69, 888–900.

Lien, E.C., Lyssiotis, C.A., and Cantley, L.C. (2016). Metabolic reprogramming by the PI3K-Akt-mTOR pathway in cancer. In: Cramer, T., and Schmitt, A.C. eds. Metabolism in Cancer. Recent Results in Cancer Research. Cham: Springer. 39–72.

Lin, R., Elf, S., Shan, C., Kang, H.B., Ji, Q., Zhou, L., Hitosugi, T., Zhang, L., Zhang, S., Seo, J.H., et al. (2015). 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. Nat Cell Biol 17, 1484–1496.

Lindner, T., Loktev, A., Altmann, A., Giesel, F., Kratochwil, C., Debus, J., Jäger, D., Mier, W., and Haberkorn, U. (2018). Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein. J Nucl Med 59, 1415–1422.

Little, C., and O’Brien, P.J. (1969). Mechanism of peroxide-inactivation of the sulphydryl enzyme glyceraldehyde-3-phosphate dehydrogenase. Eur J Biochem 10, 533–538.

Liu, G., Parant, J.M., Lang, G., Chau, P., Chavez-Reyes, A., El-Naggar, A. K., Multani, A., Chang, S., and Lozano, G. (2004). Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet 36, 63–68.

Liu, H., Shen, Z., Wang, Z., Wang, X., Zhang, H., Qin, J., Qin, X., Xu, J., and Sun, Y. (2016a). Increased expression of IDO associates with poor postoperative clinical outcome of patients with gastric adenocarcinoma. Sci Rep 6, 21319.

Liu, L., Shah, S., Fan, J., Park, J.O., Wellen, K.E., and Rabinowitz, J.D. (2016b). Malic enzyme tracers reveal hypoxia-induced switch in adipocyte NADPH pathway usage. Nat Chem Biol 12, 345–352.

Liu, P.S., Wang, H., Li, X., Chao, T., Teav, T., Christen, S., Di Conza, G., Cheng, W.C., Chou, C.H., Vavakova, M., et al. (2017). α-Ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol 18, 985–994.

Liu, Y., Gu, Y., Han, Y., Zhang, Q., Jiang, Z., Zhang, X., Huang, B., Xu, X., Zheng, J., and Cao, X. (2016c). Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30, 243–256.

Liu, Y., Guo, J.Z., Liu, Y., Wang, K., Ding, W., Wang, H., Liu, X., Zhou, S., Lu, X.C., Yang, H.B., et al. (2018). Nuclear lactate dehydrogenase A senses ROS to produce α-hydroxybutyrate for HPV-induced cervical tumor growth. Nat Commun 9, 4429.

Liu, Y., He, Y., Jin, A., Tikunov, A.P., Zhou, L., Tollini, L.A., Leslie, P., Kim, T.H., Li, L.O., Coleman, R.A., et al. (2014). Ribosomal protein-Mdm2-p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting fatty acid oxidation. Proc Natl Acad Sci USA 111, E2414–E2422.

Locasale, J.W. (2013). Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 13, 572–583.

Lochner, M., Berod, L., and Sparwasser, T. (2015). Fatty acid metabolism in the regulation of T cell function. Trends Immunol 36, 81–91.

Locke, J.A., Guns, E.S., Lubik, A.A., Adomat, H.H., Hendy, S.C., Wood, C.A., Ettinger, S.L., Gleave, M.E., and Nelson, C.C. (2008). Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 68, 6407–6415.

Lu, C., and Thompson, C.B. (2012). Metabolic regulation of epigenetics. Cell Metab 16, 9–17.

Lu, C., Ward, P.S., Kapoor, G.S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C.R., Khanin, R., Figueroa, M.E., Melnick, A., et al. (2012). IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478.

Lu, H., Dalgard, C.L., Mohyeldin, A., McFate, T., Tait, A.S., and Verma, A. (2005). Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem 280, 41928–41939.

Lu, H., Samanta, D., Xiang, L., Zhang, H., Hu, H., Chen, I., Bullen, J.W., and Semenza, G.L. (2015). Chemotherapy triggers HIF-1-dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype. Proc Natl Acad Sci USA 112, E4600–E4609.

Lu, S.C. (2009). Regulation of glutathione synthesis. Mol Aspects Med 30, 42–59.

Luga, V., Zhang, L., Viloria-Petit, A.M., Ogunjimi, A.A., Inanlou, M.R., Chiu, E., Buchanan, M., Hosein, A.N., Basik, M., and Wrana, J.L. (2012). Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151, 1542–1556.

Ma, X., Bi, E., Huang, C., Lu, Y., Xue, G., Guo, X., Wang, A., Yang, M., Qian, J., Dong, C., et al. (2018). Cholesterol negatively regulates IL-9-producing CD8+ T cell differentiation and antitumor activity. J Exp Med 215, 1555–1569.

Ma, X., Bi, E., Lu, Y., Su, P., Huang, C., Liu, L., Wang, Q., Yang, M., Kalady, M.F., Qian, J., et al. (2019). Cholesterol induces CD8+ T cell exhaustion in the tumor microenvironment. Cell Metab 30, 143–156.e5.

Ma, X., Wang, L., Huang, D., Li, Y., Yang, D., Li, T., Li, F., Sun, L., Wei, H., He, K., et al. (2017). Polo-like kinase 1 coordinates biosynthesis during cell cycle progression by directly activating pentose phosphate pathway. Nat Commun 8, 1506.

Macfarlane, S., and Macfarlane, G.T. (2003). Regulation of short-chain fatty acid production. Proc Nutr Soc 62, 67–72.

Macintyre, A.N., Gerriets, V.A., Nichols, A.G., Michalek, R.D., Rudolph, M.C., Deoliveira, D., Anderson, S.M., Abel, E.D., Chen, B.J., Hale, L. P., et al. (2014). The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20, 61–72.

MacIver, N.J., Michalek, R.D., and Rathmell, J.C. (2013). Metabolic regulation of T lymphocytes. Annu Rev Immunol 31, 259–283.

Madureira, P.A., Hill, R., Miller, V.A., Giacomantonio, C., Lee, P.W.K., and Waisman, D.M. (2011). Annexin A2 is a novel cellular redox regulatory protein involved in tumorigenesis. Oncotarget 2, 1075–1093.

Mahic, M., Yaqub, S., Johansson, C.C., Taskén, K., and Aandahl, E.M. (2006). FOXP3+CD4+CD25+ adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by a prostaglandin E2-dependent mechanism. J Immunol 177, 246–254.

Maj, T., Wang, W., Crespo, J., Zhang, H., Wang, W., Wei, S., Zhao, L., Vatan, L., Shao, I., Szeliga, W., et al. (2017). Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol 18, 1332–1341.

Maller, C., Schröder, E., and Eaton, P. (2011). Glyceraldehyde 3-phosphate dehydrogenase is unlikely to mediate hydrogen peroxide signaling: studies with a novel anti-dimedone sulfenic acid antibody. Antioxid Redox Signal 14, 49–60.

Mandapathil, M., Szczepanski, M.J., Szajnik, M., Ren, J., Lenzner, D.E., Jackson, E.K., Gorelik, E., Lang, S., Johnson, J.T., and Whiteside, T.L. (2009). Increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer. Clin Cancer Res 15, 6348–6357.

Mannava, S., Grachtchouk, V., Wheeler, L.J., Im, M., Zhuang, D., Slavina, E.G., Mathews, C.K., Shewach, D.S., and Nikiforov, M.A. (2008). Direct role of nucleotide metabolism in c-MYC-dependent proliferation of melanoma cells. Cell Cycle 7, 2392–2400.

Marçais, A., Cherfils-Vicini, J., Viant, C., Degouve, S., Viel, S., Fenis, A., Rabilloud, J., Mayol, K., Tavares, A., Bienvenu, J., et al. (2014). The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol 15, 749–757.

Matoba, S., Kang, J.G., Patino, W.D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P.J., Bunz, F., and Hwang, P.M. (2006). p53 regulates mitochondrial respiration. Science 312, 1650–1653.

Mayers, J.R., Wu, C., Clish, C.B., Kraft, P., Torrence, M.E., Fiske, B.P., Yuan, C., Bao, Y., Townsend, M.K., Tworoger, S.S., et al. (2014). Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med 20, 1193–1198.

Mehla, K., and Singh, P.K. (2019). Metabolic regulation of macrophage polarization in cancer. Trends Cancer 5, 822–834.

Menk, A.V., Scharping, N.E., Moreci, R.S., Zeng, X., Guy, C., Salvatore, S., Bae, H., Xie, J., Young, H.A., Wendell, S.G., et al. (2018). Early TCR signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep 22, 1509–1521.

Mezrich, J.D., Fechner, J.H., Zhang, X., Johnson, B.P., Burlingham, W.J., and Bradfield, C.A. (2010). An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 185, 3190–3198.

Michalek, R.D., Gerriets, V.A., Jacobs, S.R., Macintyre, A.N., MacIver, N. J., Mason, E.F., Sullivan, S.A., Nichols, A.G., and Rathmell, J.C. (2011). Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 186, 3299–3303.

Mishra, P.J., Mishra, P.J., Humeniuk, R., Medina, D.J., Alexe, G., Mesirov, J.P., Ganesan, S., Glod, J.W., and Banerjee, D. (2008). Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res 68, 4331–4339.

Miska, J., Lee-Chang, C., Rashidi, A., Muroski, M.E., Chang, A.L., Lopez-Rosas, A., Zhang, P., Panek, W.K., Cordero, A., Han, Y., et al. (2019). HIF-1α is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep 27, 226–237.e4.

Molnár, E., Swamy, M., Holzer, M., Beck-García, K., Worch, R., Thiele, C., Guigas, G., Boye, K., Luescher, I.F., Schwille, P., et al. (2012). Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering. J Biol Chem 287, 42664–42674.

Morais, R., Zinkewich-Péotti, K., Parent, M., Wang, H., Babai, F., and Zollinger, M. (1994). Tumor-forming ability in athymic nude-mice of human cell-lines devoid of mitochondrial-DNA. Cancer Res 54, 3889–3896.

Moreno-Sánchez, R., Rodríguez-Enríquez, S., Marín-Hernández, A., and Saavedra, E. (2007). Energy metabolism in tumor cells. FEBS J 274, 1393–1418.

Mu, X., Zhao, T., Xu, C., Shi, W., Geng, B., Shen, J., Zhang, C., Pan, J., Yang, J., Hu, S., et al. (2017). Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation. Oncotarget 8, 13174–13185.

Musselman, C.A., Lalonde, M.E., Côté, J., and Kutateladze, T.G. (2012). Perceiving the epigenetic landscape through histone readers. Nat Struct Mol Biol 19, 1218–1227.

Nakajima, H., Amano, W., Fujita, A., Fukuhara, A., Azuma, Y.T., Hata, F., Inui, T., and Takeuchi, T. (2007). The active site cysteine of the proapoptotic protein glyceraldehyde-3-phosphate dehydrogenase is essential in oxidative stress-induced aggregation and cell death. J Biol Chem 282, 26562–26574.

Nakaya, M., Xiao, Y., Zhou, X., Chang, J.H., Chang, M., Cheng, X., Blonska, M., Lin, X., and Sun, S.C. (2014). Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40, 692–705.

Nefedova, Y., Fishman, M., Sherman, S., Wang, X., Beg, A.A., and Gabrilovich, D.I. (2007). Mechanism of all-Trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res 67, 11021–11028.

Newton, A.C. (2001). Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev 101, 2353–2364.

Ni, C., Fang, Q.Q., Chen, W.Z., Jiang, J.X., Jiang, Z., Ye, J., Zhang, T., Yang, L., Meng, F.B., Xia, W.J., et al. (2020). Breast cancer-derived exosomes transmit lncRNA SNHG16 to induce CD73+γδ1 Treg cells. Sig Transduct Target Ther 5, 41.

Niedzwiecki, M.M., Walker, D.I., Vermeulen, R., Chadeau-Hyam, M., Jones, D.P., and Miller, G.W. (2019). The exposome: molecules to populations. Annu Rev Pharmacol Toxicol 59, 107–127.

Nieman, K.M., Kenny, H.A., Penicka, C.V., Ladanyi, A., Buell-Gutbrod, R., Zillhardt, M.R., Romero, I.L., Carey, M.S., Mills, G.B., Hotamisligil, G.S., et al. (2011). Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17, 1498–1503.

Nikiforov, M.A., Chandriani, S., O’Connell, B., Petrenko, O., Kotenko, I., Beavis, A., Sedivy, J.M., and Cole, M.D. (2002). A functional screen for Myc-responsive genes reveals serine hydroxymethyltransferase, a major source of the one-carbon unit for cell metabolism. Mol Cell Biol 22, 5793–5800.

Noushmehr, H., Weisenberger, D.J., Diefes, K., Phillips, H.S., Pujara, K., Berman, B.P., Pan, F., Pelloski, C.E., Sulman, E.P., Bhat, K.P., et al. (2010). Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522.

O’Brien, K.L., and Finlay, D.K. (2019). Immunometabolism and natural killer cell responses. Nat Rev Immunol 19, 282–290.

O’Neill, L.A.J., Kishton, R.J., and Rathmell, J. (2016). A guide to immunometabolism for immunologists. Nat Rev Immunol 16, 553–565.

Ohta, A., Kini, R., Ohta, A., Subramanian, M., Madasu, M., and Sitkovsky, M. (2012). The development and immunosuppressive functions of CD4+CD25+FoxP3+ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front Immun 3, 190.

Ohta, A., Ohta, A., Madasu, M., Kini, R., Subramanian, M., Goel, N., and Sitkovsky, M. (2009). A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments. J Immunol 183, 5487–5493.

Opitz, C.A., Litzenburger, U.M., Sahm, F., Ott, M., Tritschler, I., Trump, S., Schumacher, T., Jestaedt, L., Schrenk, D., Weller, M., et al. (2011). An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203.

Ou, Y., Wang, S.J., Jiang, L., Zheng, B., and Gu, W. (2015). p53 Proteinmediated regulation of phosphoglycerate dehydrogenase (PHGDH) is crucial for the apoptotic response upon serine starvation. J Biol Chem 290, 457–466.

Özdemir, B.C., Pentcheva-Hoang, T., Carstens, J.L., Zheng, X., Wu, C.C., Simpson, T.R., Laklai, H., Sugimoto, H., Kahlert, C., Novitskiy, S.V., et al. (2015). Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 28, 831–833.

Pacella, I., Procaccini, C., Focaccetti, C., Miacci, S., Timperi, E., Faicchia, D., Severa, M., Rizzo, F., Coccia, E.M., Bonacina, F., et al. (2018). Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc Natl Acad Sci USA 115, E6546–E6555.

Palm, W., Park, Y., Wright, K., Pavlova, N.N., Tuveson, D.A., and Thompson, C.B. (2015). The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162, 259–270.

Park, H.J., Lee, W.Y., Park, C., Hong, K.H., Kim, J.H., and Song, H. (2018). Species-specific expression of phosphoglycerate kinase 2 (PGK2) in the developing porcine testis. Theriogenology 110, 158–167.

Park, J.E., Lenter, M.C., Zimmermann, R.N., Garin-Chesa, P., Old, L.J., and Rettig, W.J. (1999). Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem 274, 36505–36512.

Parvez, S., Long, M.J.C., Poganik, J.R., and Aye, Y. (2018). Redox signaling by reactive electrophiles and oxidants. Chem Rev 118, 8798–8888.

Patsoukis, N., Bardhan, K., Chatterjee, P., Sari, D., Liu, B., Bell, L.N., Karoly, E.D., Freeman, G.J., Petkova, V., Seth, P., et al. (2015). PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 6, 6692.

Paulsen, C.E., and Carroll, K.S. (2013). Cysteine-mediated redox signaling: chemistry, biology, and tools for discovery. Chem Rev 113, 4633–4679.

Paulsen, C.E., Truong, T.H., Garcia, F.J., Homann, A., Gupta, V., Leonard, S.E., and Carroll, K.S. (2011). Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity. Nat Chem Biol 8, 57–64.

Pearce, E.L., Walsh, M.C., Cejas, P.J., Harms, G.M., Shen, H., Wang, L.S., Jones, R.G., and Choi, Y. (2009). Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107.

Peng, M., Yin, N., Chhangawala, S., Xu, K., Leslie, C.S., and Li, M.O. (2016). Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484.

Peralta, D., Bronowska, A.K., Morgan, B., Dóka, É., Van Laer, K., Nagy, P., Gräter, F., and Dick, T.P. (2015). A proton relay enhances H2O2 sensitivity of GAPDH to facilitate metabolic adaptation. Nat Chem Biol 11, 156–163.

Pollard, P.J., Brière, J.J., Alam, N.A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S.J., et al. (2005). Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14, 2231–2239.

Poprac, P., Jomova, K., Simunkova, M., Kollar, V., Rhodes, C.J., and Valko, M. (2017). Targeting free radicals in oxidative stress-related human diseases. Trends Pharmacol Sci 38, 592–607.

Port, J., Muthalagu, N., Raja, M., Ceteci, F., Monteverde, T., Kruspig, B., Hedley, A., Kalna, G., Lilla, S., Neilson, L., et al. (2018). Colorectal tumors require NUAK1 for protection from oxidative stress. Cancer Discov 8, 632–647.

Powell, J.D., Lerner, C.G., and Schwartz, R.H. (1999). Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. J Immunol 162, 2775–2784.

Procaccini, C., Carbone, F., Di Silvestre, D., Brambilla, F., De Rosa, V., Galgani, M., Faicchia, D., Marone, G., Tramontano, D., Corona, M., et al. (2016). The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity 44, 406–421.

Putker, M., Madl, T., Vos, H.R., de Ruiter, H., Visscher, M., van den Berg, M.C.W., Kaplan, M., Korswagen, H.C., Boelens, R., Vermeulen, M., et al. (2013). Redox-dependent control of FOXO/DAF-16 by transportin-1. Mol Cell 49, 730–742.

Putker, M., Vos, H.R., van Dorenmalen, K., de Ruiter, H., Duran, A.G., Snel, B., Burgering, B.M.T., Vermeulen, M., and Dansen, T.B. (2015). Evolutionary acquisition of cysteines determines FOXO paralog-specific redox signaling. Antioxid Redox Signal 22, 15–28.

Qian, X., Li, X., Cai, Q., Zhang, C., Yu, Q., Jiang, Y., Lee, J.H., Hawke, D., Wang, Y., Xia, Y., et al. (2017a). Phosphoglycerate kinase 1 phosphorylates Beclin1 to induce autophagy. Mol Cell 65, 917–931.e6.

Qian, X., Li, X., and Lu, Z. (2017b). Protein kinase activity of the glycolytic enzyme PGK1 regulates autophagy to promote tumorigenesis. Autophagy 13, 1246–1247.

Qian, X., Li, X., Shi, Z., Xia, Y., Cai, Q., Xu, D., Tan, L., Du, L., Zheng, Y., Zhao, D., et al. (2019). PTEN suppresses glycolysis by dephosphorylating and inhibiting autophosphorylated PGK1. Mol Cell 76, 516–527.e7.

Rainwater, R., Parks, D., Anderson, M.E., Tegtmeyer, P., and Mann, K. (1995). Role of cysteine residues in regulation of p53 function. Mol Cell Biol 15, 3892–3903.

Rana, S., Malinowska, K., and Zöller, M. (2013). Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia 15, 281–IN31.

Rath, M., Müller, I., Kropf, P., Closs, E.I., and Munder, M. (2014). Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front Immunol 5, 532.

Raud, B., McGuire, P.J., Jones, R.G., Sparwasser, T., and Berod, L. (2018). Fatty acid metabolism in CD8+ T cell memory: challenging current concepts. Immunol Rev 283, 213–231.

Raz, Y., Cohen, N., Shani, O., Bell, R.E., Novitskiy, S.V., Abramovitz, L., Levy, C., Milyavsky, M., Leider-Trejo, L., Moses, H.L., et al. (2018). Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer. J Exp Med 215, 3075–3093.

Reczek, C.R., and Chandel, N.S. (2015). ROS-dependent signal transduction. Curr Opin Cell Biol 33, 8–13.

Ren, W., Hou, J., Yang, C., Wang, H., Wu, S., Wu, Y., Zhao, X., and Lu, C. (2019). Extracellular vesicles secreted by hypoxia pre-challenged mesenchymal stem cells promote non-small cell lung cancer cell growth and mobility as well as macrophage M2 polarization via miR-21–5p delivery. J Exp Clin Cancer Res 38, 62.

Reynolds, M.R., Lane, A.N., Robertson, B., Kemp, S., Liu, Y., Hill, B.G., Dean, D.C., and Clem, B.F. (2014). Control of glutamine metabolism by the tumor suppressor Rb. Oncogene 33, 556–566.

Ringel, A.E., Drijvers, J.M., Baker, G.J., Catozzi, A., García-Cañaveras, J. C., Gassaway, B.M., Miller, B.C., Juneja, V.R., Nguyen, T.H., Joshi, S., et al. (2020). Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell 183, 1848–1866.e26.

Rodriguez, P.C., Quiceno, D.G., and Ochoa, A.C. (2007). L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109, 1568–1573.

Rodriguez, P.C., Quiceno, D.G., Zabaleta, J., Ortiz, B., Zea, A.H., Piazuelo, M.B., Delgado, A., Correa, P., Brayer, J., Sotomayor, E.M., et al. (2004). Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64, 5839–5849.

Röhrig, F., and Schulze, A. (2016). The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer 16, 732–749.

Roland, C.L., Arumugam, T., Deng, D., Liu, S.H., Philip, B., Gomez, S., Burns, W.R., Ramachandran, V., Wang, H., Cruz-Monserrate, Z., et al. (2014). Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Res 74, 5301–5310.

Roulis, M., Kaklamanos, A., Schernthanner, M., Bielecki, P., Zhao, J., Kaffe, E., Frommelt, L.S., Qu, R., Knapp, M.S., Henriques, A., et al. (2020). Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche. Nature 580, 524–529.

Roy, D.G., Chen, J., Mamane, V., Ma, E.H., Muhire, B.M., Sheldon, R.D., Shorstova, T., Koning, R., Johnson, R.M., Esaulova, E., et al. (2020). Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming. Cell Metab 31, 250–266.e9.

Roychoudhuri, R., Eil, R.L., Clever, D., Klebanoff, C.A., Sukumar, M., Grant, F.M., Yu, Z., Mehta, G., Liu, H., Jin, P., et al. (2016). The transcription factor BACH2 promotes tumor immunosuppression. J Clin Invest 126, 599–604.

Sabari, B.R., Tang, Z., Huang, H., Yong-Gonzalez, V., Molina, H., Kong, H.E., Dai, L., Shimada, M., Cross, J.R., Zhao, Y., et al. (2018). Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol Cell 69, 533.

Sancak, Y., Peterson, T.R., Shaul, Y.D., Lindquist, R.A., Thoreen, C.C., Bar-Peled, L., and Sabatini, D.M. (2008). The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501.

Sato, E., Olson, S.H., Ahn, J., Bundy, B., Nishikawa, H., Qian, F., Jungbluth, A.A., Frosina, D., Gnjatic, S., Ambrosone, C., et al. (2005). Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102, 18538–18543.

Sauer, S., Bruno, L., Hertweck, A., Finlay, D., Leleu, M., Spivakov, M., Knight, Z.A., Cobb, B.S., Cantrell, D., O’Connor, E., et al. (2008). T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA 105, 7797–7802.

Scharping, N.E., Menk, A.V., Moreci, R.S., Whetstone, R.D., Dadey, R.E., Watkins, S.C., Ferris, R.L., and Delgoffe, G.M. (2016). The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 374–388.

Schoenfeld, J.D., Alexander, M.S., Waldron, T.J., Sibenaller, Z.A., Spitz, D.R., Buettner, G.R., Allen, B.G., and Cullen, J.J. (2019). Pharmacological ascorbate as a means of sensitizing cancer cells to radio-chemotherapy while protecting normal tissue. Semin Radiat Oncol 29, 25–32.

Schwartzenberg-Bar-Yoseph, F., Armoni, M., and Karnieli, E. (2004). The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 64, 2627–2633.

Schwer, B., and Verdin, E. (2008). Conserved metabolic regulatory functions of sirtuins. Cell Metab 7, 104–112.

Selak, M.A., Armour, S.M., MacKenzie, E.D., Boulahbel, H., Watson, D. G., Mansfield, K.D., Pan, Y., Simon, M.C., Thompson, C.B., and Gottlieb, E. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7, 77–85.

Semenza, G.L. (2017). Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype. EMBO J 36, 252–259.

Semenza, G.L., Roth, P.H., Fang, H.M., and Wang, G.L. (1994). Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269, 23757–23763.

Shao, F., Yang, X., Wang, W., Wang, J., Guo, W., Feng, X., Shi, S., Xue, Q., Gao, S., Gao, Y., et al. (2019). Associations of PGK1 promoter hypomethylation and PGK1-mediated PDHK1 phosphorylation with cancer stage and prognosis: a TCGA pan-cancer analysis. Cancer Commun 39, 54.

Shao, W., and Espenshade, P.J. (2012). Expanding roles for SREBP in metabolism. Cell Metab 16, 414–419.

Shao, Y., Chen, T., Zheng, X., Yang, S., Xu, K., Chen, X., Xu, F., Wang, L., Shen, Y., Wang, T., et al. (2018). Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis. Carcinogenesis 39, 1368–1379.

Sharma, S., Yang, S.C., Zhu, L., Reckamp, K., Gardner, B., Baratelli, F., Huang, M., Batra, R.K., and Dubinett, S.M. (2005). Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res 65, 5211–5220.

Shen, Z.X., Chen, G.Q., Ni, J.H., Li, X.S., Xiong, S.M., Qiu, Q.Y., Zhu, J., Tang, W., Sun, G.L., Yang, K.Q., et al. (1997). Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89, 3354–3360.

Shi, L.Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D.R., and Chi, H. (2011). HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208, 1367–1376.

Shi, X., Wang, B., Feng, X., Xu, Y., Lu, K., and Sun, M. (2020). CircRNAs and exosomes: a mysterious frontier for human cancer. Mol Ther Nucleic Acids 19, 384–392.

Shim, H., Dolde, C., Lewis, B.C., Wu, C.S., Dang, G., Jungmann, R.A., Dalla-Favera, R., and Dang, C.V. (1997). c-Myc transactivation of LDH-A: Implications for tumor metabolism and growth. Proc Natl Acad Sci USA 94, 6658–6663.

Shimoda, M., Principe, S., Jackson, H.W., Luga, V., Fang, H., Molyneux, S. D., Shao, Y.W., Aiken, A., Waterhouse, P.D., Karamboulas, C., et al. (2014). Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat Cell Biol 16, 889–901.

Shindo, K., Aishima, S., Ohuchida, K., Fujiwara, K., Fujino, M., Mizuuchi, Y., Hattori, M., Mizumoto, K., Tanaka, M., and Oda, Y. (2013). Podoplanin expression in cancer-associated fibroblasts enhances tumor progression of invasive ductal carcinoma of the pancreas. Mol Cancer 12, 168.

Shyh-Chang, N., Locasale, J.W., Lyssiotis, C.A., Zheng, Y., Teo, R.Y., Ratanasirintrawoot, S., Zhang, J., Onder, T., Unternaehrer, J.J., Zhu, H., et al. (2013). Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 339, 222–226.

Sies, H., Berndt, C., and Jones, D.P. (2017). Oxidative stress. Annu Rev Biochem 86, 715–748.

Sies, H., and Jones, D.P. (2020). Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 21, 363–383.

Sinclair, L.V., Howden, A.J., Brenes, A., Spinelli, L., Hukelmann, J.L., Macintyre, A.N., Liu, X., Thomson, S., Taylor, P.M., Rathmell, J.C., et al. (2019). Antigen receptor control of methionine metabolism in T cells. eLife 8, e44210.

Sinclair, L.V., Neyens, D., Ramsay, G., Taylor, P.M., and Cantrell, D.A. (2018). Single cell analysis of kynurenine and system L amino acid transport in T cells. Nat Commun 9, 1981.

Sinclair, L.V., Rolf, J., Emslie, E., Shi, Y.B., Taylor, P.M., and Cantrell, D. A. (2013). Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 14, 500–508.

Singer, K., Gottfried, E., Kreutz, M., and Mackensen, A. (2011). Suppression of T-cell responses by tumor metabolites. Cancer Immunol Immunother 60, 425–431.

Singh, N., Gurav, A., Sivaprakasam, S., Brady, E., Padia, R., Shi, H., Thangaraju, M., Prasad, P.D., Manicassamy, S., Munn, D.H., et al. (2014). Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139.

Sivanand, S., and Vander Heiden, M.G. (2020). Emerging roles for branched-chain amino acid metabolism in cancer. Cancer Cell 37, 147–156.

Smith, P.M., Howitt, M.R., Panikov, N., Michaud, M., Gallini, C.A., Bohlooly-Y, M., Glickman, J.N., and Garrett, W.S. (2013). The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573.

Snaebjornsson, M.T., Janaki-Raman, S., and Schulze, A. (2020). Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer. Cell Metab 31, 62–76.

Snijdewint, F.G., Kaliński, P., Wierenga, E.A., Bos, J.D., and Kapsenberg, M.L. (1993). Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. J Immunol 150, 5321–5329.

Sobotta, M.C., Liou, W., Stöcker, S., Talwar, D., Oehler, M., Ruppert, T., Scharf, A.N.D., and Dick, T.P. (2015). Peroxiredoxin-2 and STAT3 form a redox relay for H2O2 signaling. Nat Chem Biol 11, 64–70.

Spinelli, J.B., Yoon, H., Ringel, A.E., Jeanfavre, S., Clish, C.B., and Haigis, M.C. (2017). Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. Science 358, 941–946.

Stegen, S., van Gastel, N., Eelen, G., Ghesquière, B., D’Anna, F., Thienpont, B., Goveia, J., Torrekens, S., Van Looveren, R., Luyten, F.P., et al. (2016). HIF-1α promotes glutamine-mediated redox homeostasis and glycogen-dependent bioenergetics to support postimplantation bone cell survival. Cell Metab 23, 265–279.

Steinbrenner, H., Speckmann, B., and Sies, H. (2013). Toward understanding success and failures in the use of selenium for cancer prevention. Antioxid Redox Signal 19, 181–191.

Stern, R., Shuster, S., Neudecker, B.A., and Formby, B. (2002). Lactate stimulates fibroblast expression of hyaluronan and CD44: The Warburg effect revisited. Exp Cell Res 276, 24–31.

Stewart, A.A., and Scopes, R.K. (1978). Phosphoglycerate kinase B from ram testis. Purification, characterisation and comparison with the muscle isoenzyme. Eur J Biochem 85, 89–95.

Stine, Z.E., Walton, Z.E., Altman, B.J., Hsieh, A.L., and Dang, C.V. (2015). MYC, metabolism, and cancer. Cancer Discov 5, 1024–1039.

Stöcker, S., Van Laer, K., Mijuskovic, A., and Dick, T.P. (2018). The conundrum of hydrogen peroxide signaling and the emerging role of peroxiredoxins as redox relay hubs. Antioxid Redox Signal 28, 558–573.

Stolzing, A., and Grune, T. (2004). Neuronal apoptotic bodies: phagocytosis and degradation by primary microglial cells. FASEB J 18, 743–745.

Stone, T.W., and Darlington, L.G. (2002). Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 1, 609–620.

Strahl, B.D., and Allis, C.D. (2000). The language of covalent histone modifications. Nature 403, 41–45.

Su, S., Chen, J., Yao, H., Liu, J., Yu, S., Lao, L., Wang, M., Luo, M., Xing, Y., Chen, F., et al. (2018). CD10+GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172, 841–856.e16.

Su, W., Chapman, N.M., Wei, J., Zeng, H., Dhungana, Y., Shi, H., Saravia, J., Zhou, P., Long, L., Rankin, S., et al. (2020). Protein prenylation drives discrete signaling programs for the differentiation and maintenance of effector Treg cells. Cell Metab 32, 996–1011.e7.

Sun, L., Song, L., Wan, Q., Wu, G., Li, X., Wang, Y., Wang, J., Liu, Z., Zhong, X., He, X., et al. (2015). cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions. Cell Res 25, 429–444.

Sun, X., Wu, Y., Gao, W., Enjyoji, K., Csizmadia, E., Müller, C.E., Murakami, T., and Robson, S.C. (2010). CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice. Gastroenterology 139, 1030–1040.

Suzuki, S., Tanaka, T., Poyurovsky, M.V., Nagano, H., Mayama, T., Ohkubo, S., Lokshin, M., Hosokawa, H., Nakayama, T., Suzuki, Y., et al. (2010). Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci USA 107, 7461–7466.

Tanaka, A., and Sakaguchi, S. (2017). Regulatory T cells in cancer immunotherapy. Cell Res 27, 109–118.

Tang, S.W., Chang, W.H., Su, Y.C., Chen, Y.C., Lai, Y.H., Wu, P.T., Hsu, C. I., Lin, W.C., Lai, M.K., and Lin, J.Y. (2009). MYC pathway is activated in clear cell renal cell carcinoma and essential for proliferation of clear cell renal cell carcinoma cells. Cancer Lett 273, 35–43.

Teng, F., Tian, W.Y., Wang, Y.M., Zhang, Y.F., Guo, F., Zhao, J., Gao, C., and Xue, F.X. (2016). Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis. J Hematol Oncol 9, 8.

Teperino, R., Schoonjans, K., and Auwerx, J. (2010). Histone methyl transferases and demethylases; can they link metabolism and transcription? Cell Metab 12, 321–327.

Thommen, D.S., Koelzer, V.H., Herzig, P., Roller, A., Trefny, M., Dimeloe, S., Kiialainen, A., Hanhart, J., Schill, C., Hess, C., et al. (2018). A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat Med 24, 994–1004.

Togashi, Y., Shitara, K., and Nishikawa, H. (2019). Regulatory T cells in cancer immunosuppression—implications for anticancer therapy. Nat Rev Clin Oncol 16, 356–371.

Tominaga, N., Kosaka, N., Ono, M., Katsuda, T., Yoshioka, Y., Tamura, K., Lötvall, J., Nakagama, H., and Ochiya, T. (2015). Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat Commun 6, 6716.

Tomlinson, I.P.M., Alam, N.A., Rowan, A.J., Barclay, E., Jaeger, E.E.M., Kelsell, D., Leigh, I., Gorman, P., Lamlum, H., Rahman, S., et al. (2002). Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30, 406–410.

Tönjes, M., Barbus, S., Park, Y.J., Wang, W., Schlotter, M., Lindroth, A.M., Pleier, S.V., Bai, A.H.C., Karra, D., Piro, R.M., et al. (2013). BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med 19, 901–908.

Trachootham, D., Alexandre, J., and Huang, P. (2009). Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8, 579–591.

Truong, T.H., Ung, P.M.U., Palde, P.B., Paulsen, C.E., Schlessinger, A., and Carroll, K.S. (2016). Molecular basis for redox activation of epidermal growth factor receptor kinase. Cell Chem Biol 23, 837–848.

Turcan, S., Rohle, D., Goenka, A., Walsh, L.A., Fang, F., Yilmaz, E., Campos, C., Fabius, A.W.M., Lu, C., Ward, P.S., et al. (2012). IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483.

Turnis, M.E., Sawant, D.V., Szymczak-Workman, A.L., Andrews, L.P., Delgoffe, G.M., Yano, H., Beres, A.J., Vogel, P., Workman, C.J., and Vignali, D.A.A. (2016). Interleukin-35 limits anti-tumor immunity. Immunity 44, 316–329.

Tyrakis, P.A., Palazon, A., Macias, D., Lee, K.L., Phan, A.T., Veliça, P., You, J., Chia, G.S., Sim, J., Doedens, A., et al. (2016). S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540, 236–241.

van der Goot, A.T., and Nollen, E.A.A. (2013). Tryptophan metabolism: entering the field of aging and age-related pathologies. Trends Mol Med 19, 336–344.

van der Reest, J., Lilla, S., Zheng, L., Zanivan, S., and Gottlieb, E. (2018). Proteome-wide analysis of cysteine oxidation reveals metabolic sensitivity to redox stress. Nat Commun 9, 1581.

van der Windt, G.J.W., Everts, B., Chang, C.H., Curtis, J.D., Freitas, T.C., Amiel, E., Pearce, E.J., and Pearce, E.L. (2012). Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78.

van der Windt, G.J.W., and Pearce, E.L. (2012). Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev 249, 27–42.

van Niel, G., D’Angelo, G., and Raposo, G. (2018). Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 19, 213–228.

Velu, C.S., Niture, S.K., Doneanu, C.E., Pattabiraman, N., and Srivenugopal, K.S. (2007). Human p53 is inhibited by glutathionylation of cysteines present in the proximal DNA-binding domain during oxidative stress. Biochemistry 46, 7765–7780.

Venneti, S., Dunphy, M.P., Zhang, H., Pitter, K.L., Zanzonico, P., Campos, C., Carlin, S.D., La Rocca, G., Lyashchenko, S., Ploessl, K., et al. (2015). Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo. Sci Transl Med 7, 274ra17.

Vogelstein, B., and Kinzler, K.W. (2004). Cancer genes and the pathways they control. Nat Med 10, 789–799.

Wallace, C., and Keast, D. (1992). Glutamine and macrophage function. Metabolism 41, 1016–1020.

Wang, D., and Dubois, R.N. (2010). Eicosanoids and cancer. Nat Rev Cancer 10, 181–193.

Wang, F., Li, L., Piontek, K., Sakaguchi, M., and Selaru, F.M. (2018). Exosome miR-335 as a novel therapeutic strategy in hepatocellular carcinoma. Hepatology 67, 940–954.

Wang, G., Liu, W., Zou, Y., Wang, G., Deng, Y., Luo, J., Zhang, Y., Li, H., Zhang, Q., Yang, Y., et al. (2019a). Three isoforms of exosomal circPTGR1 promote hepatocellular carcinoma metastasis via the miR449a-MET pathway. Ebiomedicine 40, 432–445.

Wang, H., Franco, F., and Ho, P.C. (2017). Metabolic regulation of tregs in cancer: opportunities for immunotherapy. Trends Cancer 3, 583–592.

Wang, H., Franco, F., Tsui, Y.C., Xie, X., Trefny, M.P., Zappasodi, R., Mohmood, S.R., Fernández-García, J., Tsai, C.H., Schulze, I., et al. (2020). CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol 21, 298–308.

Wang, K., Jiang, J., Lei, Y., Zhou, S., Wei, Y., and Huang, C. (2019b). Targeting metabolic-redox circuits for cancer therapy. Trends Biochem Sci 44, 401–414.

Wang, K., Zhang, T., Dong, Q., Nice, E.C., Huang, C., and Wei, Y. (2013a). Redox homeostasis: the linchpin in stem cell self-renewal and differentiation. Cell Death Dis 4, e537.

Wang, M.C., O’Rourke, E.J., and Ruvkun, G. (2008). Fat metabolism links germline stem cells and longevity in C. elegans. Science 322, 957–960.

Wang, P., Dong, Q., Zhang, C., Kuan, P.F., Liu, Y., Jeck, W.R., Andersen, J. B., Jiang, W., Savich, G.L., Tan, T.X., et al. (2013b). Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 32, 3091–3100.

Wang, R., Dillon, C.P., Shi, L.Z., Milasta, S., Carter, R., Finkelstein, D., McCormick, L.L., Fitzgerald, P., Chi, H., Munger, J., et al. (2011). The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882.

Wang, W., and Zou, W. (2020). Amino acids and their transporters in T cell immunity and cancer therapy. Mol Cell 80, 384–395.

Wang, W.L., Jiang, Z.R., Hu, C., Chen, C., Hu, Z.Q., Wang, A.L., Wang, L., Liu, J., Wang, W.C., and Liu, Q.S. (2021). Pharmacologically inhibiting phosphoglycerate kinase 1 for glioma with NG52. Acta Pharmacol Sin 42, 633–640.

Wang, X., Liu, R., Qu, X., Yu, H., Chu, H., Zhang, Y., Zhu, W., Wu, X., Gao, H., Tao, B., et al. (2019c). α-Ketoglutarate-activated NF-κB signaling promotes compensatory glucose uptake and brain tumor development. Mol Cell 76, 148–162.e7.

Wang, X., Liu, R., Zhu, W., Chu, H., Yu, H., Wei, P., Wu, X., Zhu, H., Gao, H., Liang, J., et al. (2019d). UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis. Nature 571, 127–131.

Warburg, O. (1956). On the origin of cancer cells. Science 123, 309–314.

Warburg, O., Wind, F., and Negelein, E. (1927). The metabolism of tumors in the body. J General Physiol 8, 519–530.

Ward, P.S., Patel, J., Wise, D.R., Abdel-Wahab, O., Bennett, B.D., Coller, H.A., Cross, J.R., Fantin, V.R., Hedvat, C.V., Perl, A.E., et al. (2010). The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234.

Watson, M.L.J., Vignali, P.D.A., Mullett, S.J., Overacre-Delgoffe, A.E., Peralta, R.M., Grebinoski, S., Menk, A.V., Rittenhouse, N.L., DePeaux, K., Whetstone, R.D., et al. (2021). Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591, 645–651.

Weinberg, F., Hamanaka, R., Wheaton, W.W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G.M., Budinger, G.R.S., and Chandel, N.S. (2010). Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA 107, 8788–8793.

Werner, A., Amann, E., Schnitzius, V., Habermeier, A., Luckner-Minden, C., Leuchtner, N., Rupp, J., Closs, E.I., and Munder, M. (2016). Induced arginine transport via cationic amino acid transporter-1 is necessary for human T-cell proliferation. Eur J Immunol 46, 92–103.

Wise, D.R., DeBerardinis, R.J., Mancuso, A., Sayed, N., Zhang, X.Y., Pfeiffer, H.K., Nissim, I., Daikhin, E., Yudkoff, M., McMahon, S.B., et al. (2008). Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 105, 18782–18787.

Won, W.J., Deshane, J.S., Leavenworth, J.W., Oliva, C.R., and Griguer, C. E. (2019). Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma. CST 3, 47–65.

Wortzel, I., Dror, S., Kenific, C.M., and Lyden, D. (2019). Exosome-mediated metastasis: communication from a distance. Dev Cell 49, 347–360.

Wu, G., and Morris, S.M. Jr. (1998). Arginine metabolism: nitric oxide and beyond. Biochem J 336, 1–17.

Wu, Y., Deng, Y., Zhu, J., Duan, Y., Weng, W.W., and Wu, X. (2018). Pim1 promotes cell proliferation and regulates glycolysis via interaction with MYC in ovarian cancer. Onco Targets Ther 11, 6647–6656.

Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., et al. (2012). Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 26, 1326–1338.

Xu, H., Xia, Y.K., Li, C.J., Zhang, J.Y., Liu, Y., Yi, W., Qin, Z.Y., Chen, L., Shi, Z.F., Quan, K., et al. (2019). Rapid diagnosis of IDH1-mutated gliomas by 2-HG detection with gas chromatography mass spectrometry. Lab Invest 99, 588–598.

Xu, K., Yin, N., Peng, M., Stamatiades, E.G., Shyu, A., Li, P., Zhang, X., Do, M.H., Wang, Z., Capistrano, K.J., et al. (2021). Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity. Science 371, 405–410.

Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.H., Ito, S., Yang, C., Wang, P., Xiao, M.T., et al. (2011). Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30.

Xu, Y.E., Wang, N., Ding, Y., Wang, C., Yu, Y., Liu, S., Wang, X., and Li, Z. (2013). Ammonium chloride enhances cisplatin cytotoxicity through DNA double-strand breaks in human cervical cancer cells. Oncol Rep 30, 1195–1200.

Xue, M., Chen, W., Xiang, A., Wang, R., Chen, H., Pan, J., Pang, H., An, H., Wang, X., Hou, H., et al. (2017). Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1. Mol Cancer 16, 143.

Yahagi, N., Shimano, H., Matsuzaka, T., Najima, Y., Sekiya, M., Nakagawa, Y., Ide, T., Tomita, S., Okazaki, H., Tamura, Y., et al. (2003). p53 Activation in adipocytes of obese mice. J Biol Chem 278, 25395–25400.

Yamamoto, M., Kensler, T.W., and Motohashi, H. (2018). The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev 98, 1169–1203.

Yan, W., Wu, X., Zhou, W., Fong, M.Y., Cao, M., Liu, J., Liu, X., Chen, C. H., Fadare, O., Pizzo, D.P., et al. (2018). Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nat Cell Biol 20, 597–609.

Yang, H., Geng, Y. H., Wang, P., Zhou, Y. T., Yang, H., Huo, Y. F., Zhang, H. Q., Li, Y., He, H.Y., Tian, X.X., et al. (2019). Extracellular ATP promotes breast cancer invasion and epithelial-mesenchymal transition via hypoxia-inducible factor 2α signaling. Cancer Sci 110, 2456–2470.

Yang, H., Villani, R.M., Wang, H., Simpson, M.J., Roberts, M.S., Tang, M., and Liang, X. (2018). The role of cellular reactive oxygen species in cancer chemotherapy. J Exp Clin Cancer Res 37, 266.

Yang, L., Achreja, A., Yeung, T.L., Mangala, L.S., Jiang, D., Han, C., Baddour, J., Marini, J.C., Ni, J., Nakahara, R., et al. (2016a). Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metab 24, 685–700.

Yang, M., Chen, S., Du, J., He, J., Wang, Y., Li, Z., Liu, G., Peng, W., Zeng, X., Li, D., et al. (2016b). NK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation. Nat Commun 7, 12730.

Yang, W., Bai, Y., Xiong, Y., Zhang, J., Chen, S., Zheng, X., Meng, X., Li, L., Wang, J., Xu, C., et al. (2016c). Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 531, 651–655.

Ye, D., Guan, K.L., and Xiong, Y. (2018). Metabolism, activity, and targeting of D- and L-2-hydroxyglutarates. Trends Cancer 4, 151–165.

Ye, T., Liang, Y., Zhang, D., and Zhang, X. (2021). Corrigendum: microRNA-16–1-3p represses breast tumor growth and metastasis by inhibiting PGK1-mediated Warburg effect. Front Cell Dev Biol 9, 649787.

Ye, Y., Li, S.L., Ma, Y.Y., Diao, Y.J., Yang, L., Su, M.Q., Li, Z., Ji, Y., Wang, J., Lei, L., et al. (2017). Exosomal miR-141–3p regulates osteoblast activity to promote the osteoblastic metastasis of prostate cancer. Oncotarget 8, 94834–94849.

Ying, H., Kimmelman, A.C., Lyssiotis, C.A., Hua, S., Chu, G.C., Fletcher-Sananikone, E., Locasale, J.W., Son, J., Zhang, H., Coloff, J.L., et al. (2012). Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670.

Yu, T., Zhao, Y., Hu, Z., Li, J., Chu, D., Zhang, J., Li, Z., Chen, B., Zhang, X., Pan, H., et al. (2017). MetaLnc9 facilitates lung cancer metastasis via a PGK1-activated AKT/mTOR pathway. Cancer Res 77, 5782–5794.

Yu, X., Lao, Y., Teng, X.L., Li, S., Zhou, Y., Wang, F., Guo, X., Deng, S., Chang, Y., Wu, X., et al. (2018a). SENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation. Nat Commun 9, 3157.

Yu, X., Teng, X.L., Wang, F., Zheng, Y., Qu, G., Zhou, Y., Hu, Z., Wu, Z., Chang, Y., Chen, L., et al. (2018b). Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome. J Exp Med 215, 2463–2476.

Yuan, K., Lei, Y., Chen, H.N., Chen, Y., Zhang, T., Li, K., Xie, N., Wang, K., Feng, X., Pu, Q., et al. (2016). HBV-induced ROS accumulation promotes hepatocarcinogenesis through Snail-mediated epigenetic silencing of SOCS3. Cell Death Differ 23, 616–627.

Yue, M., Jiang, J., Gao, P., Liu, H., and Qing, G. (2017). Oncogenic MYC activates a feedforward regulatory loop promoting essential amino acid metabolism and tumorigenesis. Cell Rep 21, 3819–3832.

Yun, J., Mullarky, E., Lu, C., Bosch, K.N., Kavalier, A., Rivera, K., Roper, J., Chio, I.I.C., Giannopoulou, E.G., Rago, C., et al. (2015). Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350, 1391–1396.

Yusuf, M.A., Chuang, T., Bhat, G.J., and Srivenugopal, K.S. (2010). Cys-141 glutathionylation of human p53: Studies using specific polyclonal antibodies in cancer samples and cell lines. Free Radic Biol Med 49, 908–917.

Zang, X., Gu, J., Zhang, J., Shi, H., Hou, S., Xu, X., Chen, Y., Zhang, Y., Mao, F., Qian, H., et al. (2020). Exosome-transmitted lncRNA UFC1 promotes non-small-cell lung cancer progression by EZH2-mediated epigenetic silencing of PTEN expression. Cell Death Dis 11, 215.

Zelenay, S., van der Veen, A.G., Böttcher, J.P., Snelgrove, K.J., Rogers, N., Acton, S.E., Chakravarty, P., Girotti, M.R., Marais, R., Quezada, S.A., et al. (2015). Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270.

Zeng, H., and Chi, H. (2017). mTOR signaling in the differentiation and function of regulatory and effector T cells. Curr Opin Immunol 46, 103–111.

Zeng, Z., Li, Y., Pan, Y., Lan, X., Song, F., Sun, J., Zhou, K., Liu, X., Ren, X., Wang, F., et al. (2018). Cancer-derived exosomal miR-25–3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun 9, 5395.

Zhang, C., Yue, C., Herrmann, A., Song, J., Egelston, C., Wang, T., Zhang, Z., Li, W., Lee, H., Aftabizadeh, M., et al. (2020). STAT3 activation-induced fatty acid oxidation in CD8+ T effector cells is critical for obesity-promoted breast tumor growth. Cell Metab 31, 148–161.e5.

Zhang, D., Tang, Z., Huang, H., Zhou, G., Cui, C., Weng, Y., Liu, W., Kim, S., Lee, S., Perez-Neut, M., et al. (2019). Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580.

Zhang, D., Wang, Y., Shi, Z., Liu, J., Sun, P., Hou, X., Zhang, J., Zhao, S., Zhou, B.P., and Mi, J. (2015a). Metabolic reprogramming of cancer-associated fibroblasts by IDH3α downregulation. Cell Rep 10, 1335–1348.

Zhang, H.M., Li, Q., Zhu, X., Liu, W., Hu, H., Liu, T., Cheng, F., You, Y., Zhong, Z., Zou, P., et al. (2016). miR-146b-5p within BCR-ABL1-positive microvesicles promotes leukemic transformation of hematopoietic cells. Cancer Res 76, 2901–2911.

Zhang, L., Zhang, S., Yao, J., Lowery, F.J., Zhang, Q., Huang, W.C., Li, P., Li, M., Wang, X., Zhang, C., et al. (2015b). Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104.

Zhang, P., Zhou, H., Lu, K., Lu, Y., Wang, Y., and Feng, T. (2018a). Exosome-mediated delivery of MALAT1 induces cell proliferation in breast cancer. Onco Targets Ther 11, 291–299.

Zhang, X.W., Yan, X.J., Zhou, Z.R., Yang, F.F., Wu, Z.Y., Sun, H.B., Liang, W.X., Song, A.X., Lallemand-Breitenbach, V., Jeanne, M., et al. (2010). Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science 328, 240–243.

Zhang, Y., Kurupati, R., Liu, L., Zhou, X.Y., Zhang, G., Hudaihed, A., Filisio, F., Giles-Davis, W., Xu, X., Karakousis, G.C., et al. (2017). Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32, 377–391.e9.

Zhang, Y., Yu, G., Chu, H., Wang, X., Xiong, L., Cai, G., Liu, R., Gao, H., Tao, B., Li, W., et al. (2018b). Macrophage-associated PGK1 phosphorylation promotes aerobic glycolysis and tumorigenesis. Mol Cell 71, 201–215.e7.

Zhao, F., Xiao, C., Evans, K.S., Theivanthiran, T., DeVito, N., Holtzhausen, A., Liu, J., Liu, X., Boczkowski, D., Nair, S., et al. (2018). Paracrine Wnt5a-β-catenin signaling triggers a metabolic program that drives dendritic cell tolerization. Immunity 48, 147–160.e7.

Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., et al. (2009). Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324, 261–265.

Zheng, X., Koropatnick, J., Chen, D., Velenosi, T., Ling, H., Zhang, X., Jiang, N., Navarro, B., Ichim, T.E., Urquhart, B., et al. (2013). Silencing IDO in dendritic cells: a novel approach to enhance cancer immunotherapy in a murine breast cancer model. Int J Cancer 132, 967–977.

Zhou, W., Fong, M.Y., Min, Y., Somlo, G., Liu, L., Palomares, M.R., Yu, Y., Chow, A., O’Connor, S.T.F., Chin, A.R., et al. (2014). Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25, 501–515.

Zhou, X., Yan, T., Huang, C., Xu, Z., Wang, L., Jiang, E., Wang, H., Chen, Y., Liu, K., Shao, Z., et al. (2018). Melanoma cell-secreted exosomal miR-155–5p induce proangiogenic switch of cancer-associated fibroblasts via SOCS1/JAK2/STAT3 signaling pathway. J Exp Clin Cancer Res 37, 242.

Zhou, Y., Bian, S., Zhou, X., Cui, Y., Wang, W., Wen, L., Guo, L., Fu, W., and Tang, F. (2020). Single-cell multiomics sequencing reveals prevalent genomic alterations in tumor stromal cells of human colorectal cancer. Cancer Cell 38, 818–828.e5.