Maley CC, Aktipis A, Graham TA, Sottoriva A, Boddy AM, Janiszewska M, et al. Classifying the evolutionary and ecological features of neoplasms. Nat Rev Cancer. 2017;17:605–19.
Yuan S, Almagro J, Fuchs E. Beyond genetics: driving cancer with the tumour microenvironment behind the wheel. Nat Rev Cancer. 2024;24:274–86.
Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46.
Fendt SM. 100 years of the Warburg effect: a cancer metabolism endeavor. Cell. 2024;187:3824–8.
DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab. 2020;2:127–9.
Kim J, DeBerardinis RJ. Mechanisms and implications of metabolic heterogeneity in cancer. Cell Metab. 2019;30:434–46.
Ju YS, Alexandrov LB, Gerstung M, Martincorena I, Nik-Zainal S, Ramakrishna M, et al. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. Elife. 2014;3:1–28.
Chen YJ, Mahieu NG, Huang X, Singh M, Crawford PA, Johnson SL, et al. Lactate metabolism is associated with mammalian mitochondria. Nat Chem Biol. 2016;12:937–43.
Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118:3930–42.
DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016;2:e1600200.
Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression. Science. 2020;368:1–26.
Kold-Christensen R, Johannsen M. Methylglyoxal metabolism and aging-related disease: moving from correlation toward causation. Trends Endocrinol Metab. 2020;31:81–92.
Kong LR, Gupta K, Wu AJ, Perera D, Ivanyi-Nagy R, Ahmed SM, et al. A glycolytic metabolite bypasses “two-hit” tumor suppression by BRCA2. Cell. 2024;187:2269–87.e16.
Baumann T, Dunkel A, Schmid C, Schmitt S, Hiltensperger M, Lohr K, et al. Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal. Nat Immunol. 2020;21:555–66.
Foskolou IP, Bunse L, Van den Bossche J. 2-hydroxyglutarate rides the cancer-immunity cycle. Curr Opin Biotechnol. 2023;83:102976.
Oldham WM, Clish CB, Yang Y, Loscalzo J. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 2015;22:291–303.
Intlekofer AM, Dematteo RG, Venneti S, Finley LW, Lu C, Judkins AR, et al. Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab. 2015;22:304–11.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–73.
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12.
Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–66.
Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722–31.
Yong C, Stewart GD, Frezza C. Oncometabolites in renal cancer. Nat Rev Nephrol. 2020;16:156–72.
Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287:848–51.
Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009;325:1139–42.
Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30:406–10.
Mishra P, Tang W, Putluri V, Dorsey TH, Jin F, Wang F, et al. ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming. J Clin Invest. 2018;128:323–40.
Colvin H, Nishida N, Konno M, Haraguchi N, Takahashi H, Nishimura J, et al. Oncometabolite D-2-hydroxyglurate directly induces epithelial-mesenchymal transition and is associated with distant metastasis in colorectal cancer. Sci Rep. 2016;6:36289.
Terunuma A, Putluri N, Mishra P, Mathe EA, Dorsey TH, Yi M, et al. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest. 2014;124:398–412.
Vadhan A, Yang YF, Wang YM, Chen PY, Tzou SC, Cheng KH, et al. Fumarate hydratase inhibits non-small cell lung cancer metastasis via inactivation of AMPK and upregulation of DAB2. Oncol Lett. 2023;25:42.
Shao Y, Ye G, Ren S, Piao HL, Zhao X, Lu X, et al. Metabolomics and transcriptomics profiles reveal the dysregulation of the tricarboxylic acid cycle and related mechanisms in prostate cancer. Int J Cancer. 2018;143:396–407.
Yu J, Yang H, Zhang L, Ran S, Shi Q, Peng P, et al. Effect and potential mechanism of oncometabolite succinate promotes distant metastasis of colorectal cancer by activating STAT3. BMC Gastroenterol. 2024;24:106.
Cai Y, Wang Z, Guo S, Lin C, Yao H, Yang Q, et al. Detection, mechanisms, and therapeutic implications of oncometabolites. Trends Endocrinol Metab. 2023;34:849–61.
DeBerardinis RJ, Keshari KR. Metabolic analysis as a driver for discovery, diagnosis, and therapy. Cell. 2022;185:2678–89.
Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574:575–80.
Gaffney DO, Jennings EQ, Anderson CC, Marentette JO, Shi T, Schou Oxvig AM, et al. Non-enzymatic lysine lactoylation of glycolytic enzymes. Cell Chem Biol. 2020;27:206–13.e6.
Cui H, Xie N, Banerjee S, Ge J, Jiang D, Dey T, et al. Lung myofibroblasts promote macrophage profibrotic activity through lactate-induced histone lactylation. Am J Respir Cell Mol Biol. 2021;64:115–25.
Yang K, Fan M, Wang X, Xu J, Wang Y, Tu F, et al. Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis. Cell Death Differ. 2022;29:133–46.
Yu J, Chai P, Xie M, Ge S, Ruan J, Fan X, et al. Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. Genome Biol. 2021;22:85.
Xiong J, He J, Zhu J, Pan J, Liao W, Ye H, et al. Lactylation-driven METTL3-mediated RNA m(6)A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol Cell. 2022;82:1660–77.e10.
Losman JA, Koivunen P, Kaelin WG Jr. 2-Oxoglutarate-dependent dioxygenases in cancer. Nat Rev Cancer. 2020;20:710–26.
Martinez S, Hausinger RP. Catalytic mechanisms of Fe(II)- and 2-oxoglutarate-dependent oxygenases. J Biol Chem. 2015;290:20702–11.
Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–67.
Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483:479–83.
Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, et al. 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. 2012;26:1326–38.
Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17–30.
Rahme GJ, Javed NM, Puorro KL, Xin S, Hovestadt V, Johnstone SE, et al. Modeling epigenetic lesions that cause gliomas. Cell. 2023;186:3674–85.e14.
Yang Z, Yan C, Ma J, Peng P, Ren X, Cai S, et al. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma. Nat Metab. 2023;5:61–79.
Guberovic I, Frezza C. Functional implications of fumarate-induced cysteine succination. Trends Biochem Sci. 2024;49:775–90.
Yao W, Hu X, Wang X. Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases. Signal Transduct Target Ther. 2024;9:232.
Adam J, Hatipoglu E, O’Flaherty L, Ternette N, Sahgal N, Lockstone H, et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell. 2011;20:524–37.
Ge X, Li M, Yin J, Shi Z, Fu Y, Zhao N, et al. Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma. Mol Cell. 2022;82:1249–60.e7.
Humphries F, Shmuel-Galia L, Ketelut-Carneiro N, Li S, Wang B, Nemmara VV, et al. Succination inactivates gasdermin D and blocks pyroptosis. Science. 2020;369:1633–7.
Sullivan LB, Martinez-Garcia E, Nguyen H, Mullen AR, Dufour E, Sudarshan S, et al. The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. Mol Cell. 2013;51:236–48.
Zheng L, Cardaci S, Jerby L, MacKenzie ED, Sciacovelli M, Johnson TI, et al. Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat Commun. 2015;6:6001.
Li L, Shi L, Yang S, Yan R, Zhang D, Yang J, et al. SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. Nat Commun. 2016;7:12235.
Tong Y, Guo D, Lin SH, Liang J, Yang D, Ma C, et al. SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells. Mol Cell. 2021;81:2303–16.e8.
Ma W, Sun Y, Yan R, Zhang P, Shen S, Lu H, et al. OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB. Mol Cell. 2024;84:538–51.e7.
Li F, He X, Ye D, Lin Y, Yu H, Yao C, et al. NADP(+)-IDH mutations promote hypersuccinylation that impairs mitochondria respiration and induces apoptosis resistance. Mol Cell. 2015;60:661–75.
Ahmed K, Tunaru S, Tang C, Muller M, Gille A, Sassmann A, et al. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab. 2010;11:311–9.
He W, Miao FJ, Lin DC, Schwandner RT, Wang Z, Gao J, et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004;429:188–93.
Wu JY, Huang TW, Hsieh YT, Wang YF, Yen CC, Lee GL, et al. Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor. Mol Cell. 2020;77:213–27.e5.
Elia I, Rowe JH, Johnson S, Joshi S, Notarangelo G, Kurmi K, et al. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8(+) T cells. Cell Metab. 2022;34:1137–50.e6.
Liu X, Li S, Cui Q, Guo B, Ding W, Liu J, et al. Activation of GPR81 by lactate drives tumour-induced cachexia. Nat Metab. 2024;6:708–23.
Baker SA, Rutter J. Metabolites as signalling molecules. Nat Rev Mol Cell Biol. 2023;24:355–74.
Rubic T, Lametschwandtner G, Jost S, Hinteregger S, Kund J, Carballido-Perrig N, et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol. 2008;9:1261–9.
Sabadell-Basallote J, Astiarraga B, Castano C, Ejarque M, Repolles-de-Dalmau M, Quesada I, et al. SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes. J Clin Invest. 2024;134:1–15.
Perniss A, Boonen B, Tonack S, Thiel M, Poharkar K, Alnouri MW, et al. A succinate/SUCNR1-brush cell defense program in the tracheal epithelium. Sci Adv. 2023;9:eadg8842.
Detraux D, Caruso M, Feller L, Fransolet M, Meurant S, Mathieu J, et al. A critical role for heme synthesis and succinate in the regulation of pluripotent states transitions. Elife. 2023;12:1–22.
Villanueva-Carmona T, Cedo L, Madeira A, Ceperuelo-Mallafre V, Rodriguez-Pena MM, Nunez-Roa C, et al. SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression. Cell Metab. 2023;35:601–19.e10.
Reddy A, Bozi LHM, Yaghi OK, Mills EL, Xiao H, Nicholson HE, et al. pH-Gated succinate secretion regulates muscle remodeling in response to exercise. Cell. 2020;183:62–75.e17.
Kennedy L, Glesaaen ER, Palibrk V, Pannone M, Wang W, Al-Jabri A, et al. Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia. Elife. 2022;11:1–21.
Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, et al. mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345:1250684.
Vaishnavi SN, Vlassenko AG, Rundle MM, Snyder AZ, Mintun MA, Raichle ME. Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci USA. 2010;107:17757–62.
Bhattacharya D, Azambuja AP, Simoes-Costa M. Metabolic reprogramming promotes neural crest migration via yap/tead signaling. Dev Cell. 2020;53:199–211.e6.
Moussaieff A, Rouleau M, Kitsberg D, Cohen M, Levy G, Barasch D, et al. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab. 2015;21:392–402.
Bulusu V, Prior N, Snaebjornsson MT, Kuehne A, Sonnen KF, Kress J, et al. Spatiotemporal analysis of a glycolytic activity gradient linked to mouse embryo mesoderm development. Dev Cell. 2017;40:331–41.e4.
Wicks EE, Semenza GL. Hypoxia-inducible factors: cancer progression and clinical translation. J Clin Invest. 2022;132:1–10.
Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7:77–85.
Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell. 2005;8:143–53.
Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012;483:484–8.
Notarangelo G, Spinelli JB, Perez EM, Baker GJ, Kurmi K, Elia I, et al. Oncometabolite d-2HG alters T cell metabolism to impair CD8(+) T cell function. Science. 2022;377:1519–29.
van der Windt GJ, Pearce EL. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev. 2012;249:27–42.
Feng Q, Liu Z, Yu X, Huang T, Chen J, Wang J, et al. Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity. Nat Commun. 2022;13:4981.
Sulkowski PL, Oeck S, Dow J, Economos NG, Mirfakhraie L, Liu Y, et al. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature. 2020;582:586–91.
Sulkowski PL, Sundaram RK, Oeck S, Corso CD, Liu Y, Noorbakhsh S, et al. Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat Genet. 2018;50:1086–92.
Qiu W, Hu M, Sridhar A, Opeskin K, Fox S, Shipitsin M, et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat Genet. 2008;40:650–5.
Zhou Y, Bian S, Zhou X, Cui Y, Wang W, Wen L, et al. Single-cell multiomics sequencing reveals prevalent genomic alterations in tumor stromal cells of human colorectal cancer. Cancer Cell. 2020;38:818–28.e5.
Chen Y, Wu J, Zhai L, Zhang T, Yin H, Gao H, et al. Metabolic regulation of homologous recombination repair by MRE11 lactylation. Cell. 2024;187:294–311.e21.
Chen H, Li Y, Li H, Chen X, Fu H, Mao D, et al. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Nature. 2024;631:663–9.
Glorieux C, Liu S, Trachootham D, Huang P. Targeting ROS in cancer: rationale and strategies. Nat Rev Drug Discov. 2024;23:583–606.
Tauffenberger A, Fiumelli H, Almustafa S, Magistretti PJ. Lactate and pyruvate promote oxidative stress resistance through hormetic ROS signaling. Cell Death Dis. 2019;10:653.
Hashimoto T, Hussien R, Oommen S, Gohil K, Brooks GA. Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis. FASEB J. 2007;21:2602–12.
Ali MA, Yasui F, Matsugo S, Konishi T. The lactate-dependent enhancement of hydroxyl radical generation by the Fenton reaction. Free Radic Res. 2000;32:429–38.
Apicella M, Giannoni E, Fiore S, Ferrari KJ, Fernandez-Perez D, Isella C, et al. Increased lactate secretion by cancer cells sustains non-cell-autonomous adaptive resistance to MET and EGFR targeted therapies. Cell Metab. 2018;28:848–65.e6.
Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell. 2011;20:511–23.
Jin L, Li D, Alesi GN, Fan J, Kang HB, Lu Z, et al. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell. 2015;27:257–70.
DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011;475:106–9.
Nogueira V, Hay N. Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy. Clin Cancer Res. 2013;19:4309–14.
Karagianni C, Bazopoulou D. Redox regulation in lifespan determination. J Biol Chem. 2024;300:105761.
Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21:363–83.
Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle. 2009;8:3984–4001.
Wu D, Zhuo L, Wang X. Metabolic reprogramming of carcinoma-associated fibroblasts and its impact on metabolic heterogeneity of tumors. Semin Cell Dev Biol. 2017;64:125–31.
Becker LM, O’Connell JT, Vo AP, Cain MP, Tampe D, Bizarro L, et al. Epigenetic reprogramming of cancer-associated fibroblasts deregulates glucose metabolism and facilitates progression of breast cancer. Cell Rep. 2020;31:107701.
Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De Donatis A, et al. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res. 2012;72:5130–40.
Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, et al. Lactate metabolism in human lung tumors. Cell. 2017;171:358–71.e9.
Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, et al. Glucose feeds the TCA cycle via circulating lactate. Nature. 2017;551:115–8.
Cai X, Ng CP, Jones O, Fung TS, Ryu KW, Li D, et al. Lactate activates the mitochondrial electron transport chain independently of its metabolism. Mol Cell. 2023;83:3904–20.e7.
McFarland CD, Yaglom JA, Wojtkowiak JW, Scott JG, Morse DL, Sherman MY, et al. The damaging effect of passenger mutations on cancer progression. Cancer Res. 2017;77:4763–72.
McFarland CD, Korolev KS, Kryukov GV, Sunyaev SR, Mirny LA. Impact of deleterious passenger mutations on cancer progression. Proc Natl Acad Sci USA. 2013;110:2910–5.
Castro-Giner F, Ratcliffe P, Tomlinson I. The mini-driver model of polygenic cancer evolution. Nat Rev Cancer. 2015;15:680–5.
Yue Q, Wang Z, Shen Y, Lan Y, Zhong X, Luo X, et al. Histone H3K9 lactylation confers temozolomide resistance in glioblastoma via LUC7L2-mediated MLH1 intron retention. Adv Sci. 2024;11:e2309290.
Carmona-Fontaine C, Deforet M, Akkari L, Thompson CB, Joyce JA, Xavier JB. Metabolic origins of spatial organization in the tumor microenvironment. Proc Natl Acad Sci USA. 2017;114:2934–9.
Lee DC, Sohn HA, Park ZY, Oh S, Kang YK, Lee KM, et al. A lactate-induced response to hypoxia. Cell. 2015;161:595–609.
Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011;71:2550–60.
Arner EN, Rathmell JC. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell. 2023;41:421–33.
Certo M, Tsai CH, Pucino V, Ho PC, Mauro C. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat Rev Immunol. 2021;21:151–61.
Hirschhaeuser F, Sattler UG, Mueller-Klieser W. Lactate: a metabolic key player in cancer. Cancer Res. 2011;71:6921–5.
Dhup S, Dadhich RK, Porporato PE, Sonveaux P. Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. Curr Pharm Des. 2012;18:1319–30.
Rizwan A, Serganova I, Khanin R, Karabeber H, Ni X, Thakur S, et al. Relationships between LDH-A, lactate, and metastases in 4T1 breast tumors. Clin Cancer Res. 2013;19:5158–69.
Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000;60:916–21.
Li X, Yang Y, Zhang B, Lin X, Fu X, An Y, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther. 2022;7:305.
Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med. 2018;24:1192–203.
Friedrich M, Sankowski R, Bunse L, Kilian M, Green E, Ramallo Guevara C, et al. Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas. Nat Cancer. 2021;2:723–40.
Wu MJ, Kondo H, Kammula AV, Shi L, Xiao Y, Dhiab S, et al. Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity. Science. 2024;385:eadl6173.
Cheng J, Yan J, Liu Y, Shi J, Wang H, Zhou H, et al. Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8(+) T cells in the tumor microenvironment. Cell Metab. 2023;35:961–78.e10.
Zecchini V, Paupe V, Herranz-Montoya I, Janssen J, Wortel IMN, Morris JL, et al. Fumarate induces vesicular release of mtDNA to drive innate immunity. Nature. 2023;615:499–506.
Sciacovelli M, Goncalves E, Johnson TI, Zecchini VR, da Costa AS, Gaude E, et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature. 2016;537:544–7.
Wu J, Liu N, Chen J, Tao Q, Li Q, Li J, et al. The tricarboxylic acid cycle metabolites for cancer: friend or enemy. Research. 2024;7:0351.
Valcarcel-Jimenez L, Frezza C. Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism. Br J Cancer. 2023;129:1546–57.
Eniafe J, Jiang S. The functional roles of TCA cycle metabolites in cancer. Oncogene. 2021;40:3351–63.
Kamp M, Surmacki J, Segarra Mondejar M, Young T, Chrabaszcz K, Joud F, et al. Raman micro-spectroscopy reveals the spatial distribution of fumarate in cells and tissues. Nat Commun. 2024;15:5386.
Martini T, Naef F, Tchorz JS. Spatiotemporal metabolic liver zonation and consequences on pathophysiology. Annu Rev Pathol. 2023;18:439–66.
Kumar S, Sharife H, Kreisel T, Mogilevsky M, Bar-Lev L, Grunewald M, et al. Intra-tumoral metabolic zonation and resultant phenotypic diversification are dictated by blood vessel proximity. Cell Metab. 2019;30:201–11.e6.
Li W, Wang J. Uncovering the underlying mechanisms of cancer metabolism through the landscapes and probability flux quantifications. iScience. 2020;23:101002.
Stine ZE, Schug ZT, Salvino JM, Dang CV. Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discov. 2022;21:141–62.
Bartman CR, Weilandt DR, Shen Y, Lee WD, Han Y, TeSlaa T, et al. Slow TCA flux and ATP production in primary solid tumours but not metastases. Nature. 2023;614:349–57.
Gould SJ, Lewontin RC. The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proc R Soc Lond B Biol Sci. 1979;205:581–98.
Gould SJ, Vrba ES. Exaptation – a missing term in the science of form. Paleobiology. 1982;8:4–15.
Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013;339:1621–5.
Chaturvedi A, Araujo Cruz MM, Jyotsana N, Sharma A, Goparaju R, Schwarzer A, et al. Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate. Leukemia. 2016;30:1708–15.
Kats LM, Reschke M, Taulli R, Pozdnyakova O, Burgess K, Bhargava P, et al. Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance. Cell Stem Cell. 2014;14:329–41.
Sasaki M, Knobbe CB, Munger JC, Lind EF, Brenner D, Brustle A, et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 2012;488:656–9.
Chaturvedi A, Araujo Cruz MM, Jyotsana N, Sharma A, Yun H, Gorlich K, et al. Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood. 2013;122:2877–87.
Nieto MA, Huang RY, Jackson RA, Thiery JP. Emt: 2016. Cell. 2016;166:21–45.
Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20:69–84.
Pastushenko I, Blanpain C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 2019;29:212–26.
Liu W, Wang Y, Bozi LHM, Fischer PD, Jedrychowski MP, Xiao H, et al. Lactate regulates cell cycle by remodelling the anaphase promoting complex. Nature. 2023;616:790–7.
Zong Z, Xie F, Wang S, Wu X, Zhang Z, Yang B, et al. Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis. Cell. 2024;187:2375–92.e33.