Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly - clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.

3rd Department of Surgery 1st Faculty of Medicine Charles University and University Hospital Motol Prague Czechia

Faculty of Science Charles University Prague Czechia

Institute of Biotechnology of the Czech Academy of Sciences Prague Czechia

See more in PubMed

Fendt SM. Is there a therapeutic window for metabolism-based cancer therapies? Front Endocrinol (Lausanne) (2017) 8:150. doi: 10.3389/fendo.2017.00150 PubMed DOI PMC

Liu T, Zhou L, Li D, Andl T, Zhang Y. Cancer-associated fibroblasts build and secure the tumor microenvironment. Front Cell Dev Biol (2019) 7:60. doi: 10.3389/fcell.2019.00060 PubMed DOI PMC

Kay EJ, Paterson K, Riera-Domingo C, Sumpton D, Dabritz JHM, Tardito S, et al. . Cancer-associated fibroblasts require proline synthesis by Pycr1 for the deposition of pro-tumorigenic extracellular matrix. Nat Metab (2022) 4(6):693–710. doi: 10.1038/s42255-022-00582-0 PubMed DOI PMC

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(7678):115–8. doi: 10.1038/nature24057 PubMed DOI PMC

Warburg O. On the origin of cancer cells. Science (1956) 123:309–14. doi: 10.1126/science.123.3191.309 PubMed DOI

Pavlova N, Thompson C. The emerging hallmarks of cancer metabolism. Cell Metab (2016) 23(1):27–47. doi: 10.1016/j.cmet.2015.12.006 PubMed DOI PMC

Lunt SY, Vander Heiden MG. Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol (2011) 27(1):441–64. doi: 10.1146/annurev-cellbio-092910-154237 PubMed DOI

Li J, Eu JQ, Kong LR, Wang L, Lim YC, Goh BC, et al. . Targeting metabolism in cancer cells and the tumour microenvironment for cancer therapy. Molecules (2020) 25(20):4831. doi: 10.3390/molecules25204831 PubMed DOI PMC

Pfeiffer T, Schuster S, Bonhoeffer S. Cooperation and competition in the evolution of atp-producing pathways. Science (2001) 292(5516):504–7. doi: 10.1126/science.1058079 PubMed DOI

Landau BR, Laszlo J, Stengle J, Burk D. Certain metabolic and pharmacologic effects in cancer patients given infusions of 2-Deoxy-D-Glucose. JNCI: J Natl Cancer Inst (1958) 21(3):485–94. doi: 10.1093/jnci/21.3.485 PubMed DOI

Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: Prospective of anti-glycolytic cancer therapy. Pharmacol Res (2019) 150:104511. doi: 10.1016/j.phrs.2019.104511 PubMed DOI

Zhang D, Wang Y, Shi Z, Liu J, Sun P, Hou X, et al. . Metabolic reprogramming of cancer-associated fibroblasts by Idh3α downregulation. Cell Rep (2015) 10(8):1335–48. doi: 10.1016/j.celrep.2015.02.006 PubMed DOI

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(9):107701. doi: 10.1016/j.celrep.2020.107701 PubMed DOI PMC

Fitzgerald G, Soro-Arnaiz I, De Bock K. The warburg effect in endothelial cells and its potential as an anti-angiogenic target in cancer. Front Cell Dev Biol (2018) 6:100. doi: 10.3389/fcell.2018.00100 PubMed DOI PMC

De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR, et al. . Role of Pfkfb3-driven glycolysis in vessel sprouting. Cell (2013) 154(3):651–63. doi: 10.1016/j.cell.2013.06.037 PubMed DOI

Yu P, Wilhelm K, Dubrac A, Tung JK, Alves TC, Fang JS, et al. . Fgf-dependent metabolic control of vascular development. Nature (2017) 545(7653):224–8. doi: 10.1038/nature22322 PubMed DOI PMC

Yetkin-Arik B, Vogels IMC, Nowak-Sliwinska P, Weiss A, Houtkooper RH, Van Noorden CJF, et al. . The role of glycolysis and mitochondrial respiration in the formation and functioning of endothelial tip cells during angiogenesis. Sci Rep (2019) 9(1):12608. doi: 10.1038/s41598-019-48676-2 PubMed DOI PMC

Merchan JR, Kovács K, Railsback JW, Kurtoglu M, Jing Y, Piña Y, et al. . Antiangiogenic activity of 2-Deoxy-D-Glucose. PloS One (2010) 5(10):e13699. doi: 10.1371/journal.pone.0013699 PubMed DOI PMC

Del Bufalo D, Trisciuoglio D, Scarsella M, D'Amati G, Candiloro A, Iervolino A, et al. . Lonidamine causes inhibition of angiogenesis-related endothelial cell functions. Neoplasia (2004) 6(5):513–22. doi: 10.1593/neo.04133 PubMed DOI PMC

Cantelmo AR, Conradi L-C, Brajic A, Goveia J, Kalucka J, Pircher A, et al. . Inhibition of the glycolytic activator Pfkfb3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell (2016) 30(6):968–85. doi: 10.1016/j.ccell.2016.10.006 PubMed DOI PMC

Conradi L-C, Brajic A, Cantelmo AR, Bouché A, Kalucka J, Pircher A, et al. . Tumor vessel disintegration by maximum tolerable Pfkfb3 blockade. Angiogenesis (2017) 20(4):599–613. doi: 10.1007/s10456-017-9573-6 PubMed DOI

Schoonjans CA, Mathieu B, Joudiou N, Zampieri LX, Brusa D, Sonveaux P, et al. . Targeting endothelial cell metabolism by inhibition of pyruvate dehydrogenase kinase and glutaminase-1. J Clin Med (2020) 9(10):3308. doi: 10.3390/jcm9103308 PubMed DOI PMC

Menk AV, Scharping NE, Moreci RS, Zeng X, Guy C, Salvatore S, et al. . Early tcr signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep (2018) 22(6):1509–21. doi: 10.1016/j.celrep.2018.01.040 PubMed DOI PMC

Donnelly RP, Loftus RM, Keating SE, Liou KT, Biron CA, Gardiner CM, et al. . Mtorc1-dependent metabolic reprogramming is a prerequisite for nk cell effector function. J Immunol (2014) 193(9):4477–84. doi: 10.4049/jimmunol.1401558 PubMed DOI PMC

Viola A, Munari F, Sanchez-Rodriguez R, Scolaro T, Castegna A. The metabolic signature of macrophage responses. Front Immunol (2019) 10:1462. doi: 10.3389/fimmu.2019.01462 PubMed DOI PMC

Pavlou S, Wang L, Xu H, Chen M. Higher phagocytic activity of thioglycollate-elicited peritoneal macrophages is related to metabolic status of the cells. J Inflammation (2017) 14(1):4. doi: 10.1186/s12950-017-0151-x PubMed DOI PMC

Cao Y, Rathmell JC, Macintyre AN. Metabolic reprogramming towards aerobic glycolysis correlates with greater proliferative ability and resistance to metabolic inhibition in Cd8 versus Cd4 T cells. PloS One (2014) 9(8):e104104. doi: 10.1371/journal.pone.0104104 PubMed DOI PMC

Martins CP, New LA, O'Connor EC, Previte DM, Cargill KR, Tse IL, et al. . Glycolysis inhibition induces functional and metabolic exhaustion of Cd4(+) T cells in type 1 diabetes. Front Immunol (2021) 12:669456. doi: 10.3389/fimmu.2021.669456 PubMed DOI PMC

Ho P-C, Dauz Bihuniak J, Macintyre AN, Staron M, Liu X, Amezquita R, et al. . Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell (2015) 162(6):1217–28. doi: 10.1016/j.cell.2015.08.012 PubMed DOI PMC

Chang C-H, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. . Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell (2015) 162(6):1229–41. doi: 10.1016/j.cell.2015.08.016 PubMed DOI PMC

Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, et al. . Hif1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of Th17 and treg cells. J Exp Med (2011) 208(7):1367–76. doi: 10.1084/jem.20110278 PubMed DOI PMC

Li L, Liu X, Sanders KL, Edwards JL, Ye J, Si F, et al. . Tlr8-mediated metabolic control of human treg function: A mechanistic target for cancer immunotherapy. Cell Metab (2019) 29(1):103–23.e5. doi: 10.1016/j.cmet.2018.09.020 PubMed DOI PMC

Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z, et al. . Inhibiting glycolytic metabolism enhances Cd8+ T cell memory and antitumor function. J Clin Invest (2013) 123(10):4479–88. doi: 10.1172/jci69589 PubMed DOI PMC

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(12):3930–42. doi: 10.1172/JCI36843 PubMed DOI PMC

Payen VL, Mina E, Van Hée VF, Porporato PE, Sonveaux P. Monocarboxylate transporters in cancer. Mol Metab (2020) 33:48–66. doi: 10.1016/j.molmet.2019.07.006 PubMed DOI PMC

Doherty JR, Cleveland JL. Targeting lactate metabolism for cancer therapeutics. J Clin Invest (2013) 123(9):3685–92. doi: 10.1172/jci69741 PubMed DOI PMC

Corbet C, Bastien E, Draoui N, Doix B, Mignion L, Jordan BF, et al. . Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects. Nat Commun (2018) 9(1):1208. doi: 10.1038/s41467-018-03525-0 PubMed DOI PMC

Roy A, Bera S. Caf cellular glycolysis: Linking cancer cells with the microenvironment. Tumour Biol (2016) 37(7):8503–14. doi: 10.1007/s13277-016-5049-3 PubMed DOI

Domingo-Vidal M, Whitaker-Menezes D, Mollaee M, Lin Z, Tuluc M, Philp N, et al. . Monocarboxylate transporter 4 in cancer-associated fibroblasts is a driver of aggressiveness in aerodigestive tract cancers. Front Oncol (2022) 12:906494. doi: 10.3389/fonc.2022.906494 PubMed DOI PMC

Sonveaux P, Copetti T, De Saedeleer CJ, Végran F, Verrax J, Kennedy KM, et al. . Targeting the lactate transporter Mct1 in endothelial cells inhibits lactate-induced hif-1 activation and tumor angiogenesis. PloS One (2012) 7(3):e33418. doi: 10.1371/journal.pone.0033418 PubMed DOI PMC

Bola BM, Chadwick AL, Michopoulos F, Blount KG, Telfer BA, Williams KJ, et al. . Inhibition of monocarboxylate transporter-1 (Mct1) by Azd3965 enhances radiosensitivity by reducing lactate transport. Mol Cancer Ther (2014) 13(12):2805–16. doi: 10.1158/1535-7163.mct-13-1091 PubMed DOI PMC

Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, et al. . Ldha-associated lactic acid production blunts tumor immunosurveillance by T and nk cells. Cell Metab (2016) 24(5):657–71. doi: 10.1016/j.cmet.2016.08.011 PubMed DOI

Weinberg SE, Chandel NS. Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol (2015) 11(1):9–15. doi: 10.1038/nchembio.1712 PubMed DOI PMC

Li F, Simon MC. Cancer cells don't live alone: Metabolic communication within tumor microenvironments. Dev Cell (2020) 54(2):183–95. doi: 10.1016/j.devcel.2020.06.018 PubMed DOI PMC

Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al. . Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature (2014) 513(7519):559–63. doi: 10.1038/nature13490 PubMed DOI PMC

Zhang L, Li S. Lactic acid promotes macrophage polarization through mct-Hif1α signaling in gastric cancer. Exp Cell Res (2020) 388(2):111846. doi: 10.1016/j.yexcr.2020.111846 PubMed DOI

Murray CM, Hutchinson R, Bantick JR, Belfield GP, Benjamin AD, Brazma D, et al. . Monocarboxylate transporter Mct1 is a target for immunosuppression. Nat Chem Biol (2005) 1(7):371–6. doi: 10.1038/nchembio744 PubMed DOI

Bajzikova M, Kovarova J, Coelho AR, Boukalova S, Oh S, Rohlenova K, et al. . Reactivation of dihydroorotate dehydrogenase-driven pyrimidine biosynthesis restores tumor growth of respiration-deficient cancer cells. Cell Metab (2019) 29(2):399–416.e10. doi: 10.1016/j.cmet.2018.10.014 PubMed DOI PMC

Garcia-Bermudez J, Baudrier L, La K, Zhu XG, Fidelin J, Sviderskiy VO, et al. . Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. Nat Cell Biol (2018) 20(7):775–81. doi: 10.1038/s41556-018-0118-z PubMed DOI PMC

Krall AS, Mullen PJ, Surjono F, Momcilovic M, Schmid EW, Halbrook CJ, et al. . Asparagine couples mitochondrial respiration to Atf4 activity and tumor growth. Cell Metab (2021) 33(5):1013–26 e6. doi: 10.1016/j.cmet.2021.02.001 PubMed DOI PMC

Sullivan B,L, Gui Y,D, Hosios M,A, Bush N,L, Freinkman E,H, Matthew V,G. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. . Cell (2015) 162(3):552–63. doi: 10.1016/j.cell.2015.07.017 PubMed DOI PMC

Yu M. Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers. Life Sci (2011) 89(3-4):65–71. doi: 10.1016/j.lfs.2011.05.010 PubMed DOI

Tan AS, Baty JW, Dong LF, Bezawork-Geleta A, Endaya B, Goodwin J, et al. . Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab (2015) 21(1):81–94. doi: 10.1016/j.cmet.2014.12.003 PubMed DOI

Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sanchez N, Marchesini M, et al. . Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature (2014) 514(7524):628–32. doi: 10.1038/nature13611 PubMed DOI PMC

Reznik E, Miller ML, Senbabaoglu Y, Riaz N, Sarungbam J, Tickoo SK, et al. . Mitochondrial DNA copy number variation across human cancers. Elife (2016) 20(11):2666–77. doi: 10.7554/eLife.10769 PubMed DOI PMC

Vaupel P, Mayer A. Availability, not respiratory capacity governs oxygen consumption of solid tumors. Int J Biochem Cell Biol (2012) 44(9):1477–81. doi: 10.1016/j.biocel.2012.05.019 PubMed DOI

Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, Kim J, et al. . Metabolic heterogeneity in human lung tumors. Cell (2016) 164(4):681–94. doi: 10.1016/j.cell.2015.12.034 PubMed DOI PMC

Ashton TM, McKenna WG, Kunz-Schughart LA, Higgins GS. Oxidative phosphorylation as an emerging target in cancer therapy. Clin Cancer Res (2018) 24(11):2482–90. doi: 10.1158/1078-0432.CCR-17-3070 PubMed DOI

Farhadi P, Yarani R, Dokaneheifard S, Mansouri K. The emerging role of targeting cancer metabolism for cancer therapy. Tumour Biol (2020) 42(10):1010428320965284. doi: 10.1177/1010428320965284 PubMed DOI

Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ (2005) 330(7503):1304–5. doi: 10.1136/bmj.38415.708634.F7 PubMed DOI PMC

Appleyard MV, Murray KE, Coates PJ, Wullschleger S, Bray SE, Kernohan NM, et al. . Phenformin as prophylaxis and therapy in breast cancer xenografts. Br J Cancer (2012) 106(6):1117–22. doi: 10.1038/bjc.2012.56 PubMed DOI PMC

Varughese RS, Lam WS, Marican A, Viganeshwari SH, Bhave AS, Syn NL, et al. . Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential. Cancer (2019) 125(11):1789–98. doi: 10.1002/cncr.32069 PubMed DOI

Ellinghaus P, Heisler I, Unterschemmann K, Haerter M, Beck H, Greschat S, et al. . Bay 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I. Cancer Med (2013) 2(5):611–24. doi: 10.1002/cam4.112 PubMed DOI PMC

Molina JR, Sun Y, Protopopova M, Gera S, Bandi M, Bristow C, et al. . An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat Med (2018) 24(7):1036–46. doi: 10.1038/s41591-018-0052-4 PubMed DOI

Moreira PI, Custodio J, Moreno A, Oliveira CR, Santos MS. Tamoxifen and estradiol interact with the flavin mononucleotide site of complex I leading to mitochondrial failure. J Biol Chem (2006) 281(15):10143–52. doi: 10.1074/jbc.M510249200 PubMed DOI

Guo L, Shestov AA, Worth AJ, Nath K, Nelson DS, Leeper DB, et al. . Inhibition of mitochondrial complex ii by the anticancer agent lonidamine. J Biol Chem (2016) 291(1):42–57. doi: 10.1074/jbc.M115.697516 PubMed DOI PMC

Dong LF, Freeman R, Liu J, Zobalova R, Marin-Hernandez A, Stantic M, et al. . Suppression of tumor growth in vivo by the mitocan alpha-tocopheryl succinate requires respiratory complex ii. Clin Cancer Res (2009) 15(5):1593–600. doi: 10.1158/1078-0432.CCR-08-2439 PubMed DOI

Fiorillo M, Lamb R, Tanowitz HB, Mutti L, Krstic-Demonacos M, Cappello AR, et al. . Repurposing atovaquone: Targeting mitochondrial complex iii and oxphos to eradicate cancer stem cells. Oncotarget (2016) 7(23):34084–99. doi: 10.18632/oncotarget.9122 PubMed DOI PMC

Le SB, Hailer MK, Buhrow S, Wang Q, Flatten K, Pediaditakis P, et al. . Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity. J Biol Chem (2007) 282(12):8860–72. doi: 10.1074/jbc.M611777200 PubMed DOI

Diepart C, Karroum O, Magat J, Feron O, Verrax J, Calderon PB, et al. . Arsenic trioxide treatment decreases the oxygen consumption rate of tumor cells and radiosensitizes solid tumors. Cancer Res (2012) 72(2):482–90. doi: 10.1158/0008-5472.CAN-11-1755 PubMed DOI

Corso CR, Acco A, Bach C, Bonatto SJR, de Figueiredo BC, de Souza LM. Pharmacological profile and effects of mitotane in adrenocortical carcinoma. Br J Clin Pharmacol (2021) 87(7):2698–710. doi: 10.1111/bcp.14721 PubMed DOI

Rohlenova K, Sachaphibulkij K, Stursa J, Bezawork-Geleta A, Blecha J, Endaya B, et al. . Selective disruption of respiratory supercomplexes as a new strategy to suppress Her2(High) breast cancer. Antioxid Redox Signal (2017) 26(2):84–103. doi: 10.1089/ars.2016.6677 PubMed DOI PMC

Cheng G, Zielonka J, Ouari O, Lopez M, McAllister D, Boyle K, et al. . Mitochondria-targeted analogues of metformin exhibit enhanced antiproliferative and radiosensitizing effects in pancreatic cancer cells. Cancer Res (2016) 76(13):3904–15. doi: 10.1158/0008-5472.CAN-15-2534 PubMed DOI PMC

Boukalova S, Stursa J, Werner L, Ezrova Z, Cerny J, Bezawork-Geleta A, et al. . Mitochondrial targeting of metformin enhances its activity against pancreatic cancer. Mol Cancer Ther (2016) 15(12):2875–86. doi: 10.1158/1535-7163.MCT-15-1021 PubMed DOI

Dong LF, Jameson VJ, Tilly D, Cerny J, Mahdavian E, Marin-Hernandez A, et al. . Mitochondrial targeting of vitamin e succinate enhances its pro-apoptotic and anti-cancer activity Via mitochondrial complex ii. J Biol Chem (2011) 286(5):3717–28. doi: 10.1074/jbc.M110.186643 PubMed DOI PMC

Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: Zodiac-16. Diabetes Care (2010) 33(2):322–6. doi: 10.2337/dc09-1380 PubMed DOI PMC

Pollak MN. Investigating metformin for cancer prevention and treatment: The end of the beginning. Cancer Discovery (2012) 2(9):778–90. doi: 10.1158/2159-8290.CD-12-0263 PubMed DOI

McGuinness ME, Talbert RL. Phenformin-induced lactic acidosis: A forgotten adverse drug reaction. Ann Pharmacother (1993) 27(10):1183–7. doi: 10.1177/106002809302701004 PubMed DOI

Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, et al. . Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife (2014) 3:e02242. doi: 10.7554/eLife.02242 PubMed DOI PMC

Benjamin D, Robay D, Hindupur SK, Pohlmann J, Colombi M, El-Shemerly MY, et al. . Dual inhibition of the lactate transporters Mct1 and Mct4 is synthetic lethal with metformin due to nad+ depletion in cancer cells. Cell Rep (2018) 25(11):3047–58 e4. doi: 10.1016/j.celrep.2018.11.043 PubMed DOI PMC

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(23):3984–4001. doi: 10.4161/cc.8.23.10238 PubMed DOI

Erdogan B, Ao M, White LM, Means AL, Brewer BM, Yang L, et al. . Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J Cell Biol (2017) 216(11):3799–816. doi: 10.1083/jcb.201704053 PubMed DOI PMC

D'Antongiovanni V, Martinelli S, Richter S, Canu L, Guasti D, Mello T, et al. . The microenvironment induces collective migration in sdhb-silenced mouse pheochromocytoma spheroids. Endocr Relat Cancer (2017) 24(10):555–64. doi: 10.1530/erc-17-0212 PubMed DOI PMC

Martinelli S, Amore F, Mello T, Mannelli M, Maggi M, Rapizzi E. Metformin treatment induces different response in Pheochromocytoma/Paraganglioma tumour cells and in primary fibroblasts. Cancers (Basel) (2022) 14(14):3471. doi: 10.3390/cancers14143471 PubMed DOI PMC

Martinelli S, Riverso M, Mello T, Amore F, Parri M, Simeone I, et al. . Sdhb and sdhd silenced pheochromocytoma spheroids respond differently to tumour microenvironment and their aggressiveness is inhibited by impairing stroma metabolism. Mol Cell Endocrinol (2022) 547:111594. doi: 10.1016/j.mce.2022.111594 PubMed DOI

Shao S, Zhao L, An G, Zhang L, Jing X, Luo M, et al. . Metformin suppresses hif-1alpha expression in cancer-associated fibroblasts to prevent tumor-stromal cross talk in breast cancer. FASEB J (2020) 34(8):10860–70. doi: 10.1096/fj.202000951RR PubMed DOI

Xu S, Yang Z, Jin P, Yang X, Li X, Wei X, et al. . Metformin suppresses tumor progression by inactivating stromal fibroblasts in ovarian cancer. Mol Cancer Ther (2018) 17(6):1291–302. doi: 10.1158/1535-7163.MCT-17-0927 PubMed DOI

Chen G, Yu C, Tang Z, Liu S, An F, Zhu J, et al. . Metformin suppresses gastric cancer progression through calmodulinlike protein 3 secreted from tumorassociated fibroblasts. Oncol Rep (2019) 41(1):405–14. doi: 10.3892/or.2018.6783 PubMed DOI

Diebold LP, Gil HJ, Gao P, Martinez CA, Weinberg SE, Chandel NS. Mitochondrial complex iii is necessary for endothelial cell proliferation during angiogenesis. Nat Metab (2019) 1(1):158–71. doi: 10.1038/s42255-018-0011-x PubMed DOI PMC

Schiffmann LM, Werthenbach JP, Heintges-Kleinhofer F, Seeger JM, Fritsch M, Gunther SD, et al. . Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth. Nat Commun (2020) 11(1):3653. doi: 10.1038/s41467-020-17472-2 PubMed DOI PMC

Magalhaes-Novais S, Blecha J, Naraine R, Mikesova J, Abaffy P, Pecinova A, et al. . Mitochondrial respiration supports autophagy to provide stress resistance during quiescence. Autophagy (2022) 18(10):2409–26. doi: 10.1080/15548627.2022.2038898 PubMed DOI PMC

Dong LF, Swettenham E, Eliasson J, Wang XF, Gold M, Medunic Y, et al. . Vitamin e analogues inhibit angiogenesis by selective induction of apoptosis in proliferating endothelial cells: The role of oxidative stress. Cancer Res (2007) 67(24):11906–13. doi: 10.1158/0008-5472.CAN-07-3034 PubMed DOI

Rohlena J, Dong L-F, Kluckova K, Zobalova R, Goodwin J, Tilly D, et al. . Mitochondrially targeted- A tocopheryl succinate is antiangiogenic: Potential benefit against tumor angiogenesis but caution against wound healing. Antioxidants Redox Signaling (2011) 15(12):2923–35. doi: 10.1089/ars.2011.4192 PubMed DOI PMC

Don AS, Kisker O, Dilda P, Donoghue N, Zhao X, Decollogne S, et al. . A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells. Cancer Cell (2003) 3(5):497–509. doi: 10.1016/s1535-6108(03)00109-0 PubMed DOI

Han J, Li Y, Liu X, Zhou T, Sun H, Edwards P, et al. . Metformin suppresses retinal angiogenesis and inflammation in vitro and in vivo. PloS One (2018) 13(3):e0193031. doi: 10.1371/journal.pone.0193031 PubMed DOI PMC

Dallaglio K, Bruno A, Cantelmo AR, Esposito AI, Ruggiero L, Orecchioni S, et al. . Paradoxic effects of metformin on endothelial cells and angiogenesis. Carcinogenesis (2014) 35(5):1055–66. doi: 10.1093/carcin/bgu001 PubMed DOI PMC

Wang JC, Li GY, Wang B, Han SX, Sun X, Jiang YN, et al. . Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization Via pdgf-b downregulation. J Exp Clin Cancer Res (2019) 38(1):235. doi: 10.1186/s13046-019-1211-2 PubMed DOI PMC

Li M, Yu X, Li W, Liu T, Deng G, Liu W, et al. . Deguelin suppresses angiogenesis in human hepatocellular carcinoma by targeting hgf-C-Met pathway. Oncotarget (2018) 9(1):152–66. doi: 10.18632/oncotarget.22077 PubMed DOI PMC

Weinberg SE, Singer BD, Steinert EM, Martinez CA, Mehta MM, Martinez-Reyes I, et al. . Mitochondrial complex iii is essential for suppressive function of regulatory T cells. Nature (2019) 565(7740):495–9. doi: 10.1038/s41586-018-0846-z PubMed DOI PMC

Kunisada Y, Eikawa S, Tomonobu N, Domae S, Uehara T, Hori S, et al. . Attenuation of Cd4(+)Cd25(+) regulatory T cells in the tumor microenvironment by metformin, a type 2 diabetes drug. EBioMedicine (2017) 25:154–64. doi: 10.1016/j.ebiom.2017.10.009 PubMed DOI PMC

Stemberkova-Hubackova S, Zobalova R, Dubisova M, Smigova J, Dvorakova S, Korinkova K, et al. . Simultaneous targeting of mitochondrial metabolism and immune checkpoints as a new strategy for renal cancer therapy. Clin Transl Med (2022) 12(3):e645. doi: 10.1002/ctm2.645 PubMed DOI PMC

Liu Q, Tong D, Liu G, Gao J, Wang LA, Xu J, et al. . Metformin inhibits prostate cancer progression by targeting tumor-associated inflammatory infiltration. Clin Cancer Res (2018) 24(22):5622–34. doi: 10.1158/1078-0432.CCR-18-0420 PubMed DOI

Wang JC, Sun X, Ma Q, Fu GF, Cong LL, Zhang H, et al. . Metformin's antitumour and anti-angiogenic activities are mediated by skewing macrophage polarization. J Cell Mol Med (2018) 22(8):3825–36. doi: 10.1111/jcmm.13655 PubMed DOI PMC

Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U.S.A. (2015) 112(6):1809–14. doi: 10.1073/pnas.1417636112 PubMed DOI PMC

Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, et al. . Metformin promotes antitumor immunity Via endoplasmic-Reticulum-Associated degradation of pd-L1. Mol Cell (2018) 71(4):606–20 e7. doi: 10.1016/j.molcel.2018.07.030 PubMed DOI PMC

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(5454):848–51. doi: 10.1126/science.287.5454.848 PubMed DOI

Pasini B, Stratakis CA. Sdh mutations in tumorigenesis and inherited endocrine tumours: Lesson from the phaeochromocytoma-paraganglioma syndromes. J Internal Med (2009) 266(1):19–42. doi: 10.1111/j.1365-2796.2009.02111.x PubMed DOI PMC

Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, et al. . Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci (2001) 98(6):3387–92. doi: 10.1073/pnas.051633798 PubMed DOI PMC

Parsons DW, Jones SN, Zhang X, Lin JC-H, Leary RJ, Angenendt P, et al. . An integrated genomic analysis of human glioblastoma multiforme. Science (2008) 321(5897):1807–12. doi: 10.1126/science.1164382 PubMed DOI PMC

Hadrava Vanova K, Pang Y, Krobova L, Kraus M, Nahacka Z, Boukalova S, et al. . Germline Suclg2 variants in patients with pheochromocytoma and paraganglioma. J Natl Cancer Inst (2022) 114(1):130–8. doi: 10.1093/jnci/djab158 PubMed DOI PMC

Waitkus MS, Diplas BH, Yan H. Biological role and therapeutic potential of idh mutations in cancer. Cancer Cell (2018) 34(2):186–95. doi: 10.1016/j.ccell.2018.04.011 PubMed DOI PMC

Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, et al. . The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep (2011) 12(5):463–9. doi: 10.1038/embor.2011.43 PubMed DOI PMC

Stein EM, Fathi AT, DiNardo CD, Pollyea DA, Roboz GJ, Collins R, et al. . Enasidenib in patients with mutant Idh2 myelodysplastic syndromes: A phase 1 subgroup analysis of the multicentre, Ag221-C-001 trial. Lancet Haematol (2020) 7(4):e309–e19. doi: 10.1016/S2352-3026(19)30284-4 PubMed DOI

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(6):722–31. doi: 10.1182/blood-2017-04-779405 PubMed DOI PMC

Mao MJ, Leonardi DE. Vascular-endothelial response to Idh1 mutant fibrosarcoma secretome and metabolite: Implications on cancer microenvironment. Am J Cancer Res (2019) 9(1):122–33. PubMed PMC

Seok J, Yoon SH, Lee SH, Jung JH, Lee YM. The oncometabolite D−2−Hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway. Int J Oncol (2019) 54(2):753–63. doi: 10.3892/ijo.2018.4649 PubMed DOI

Zhang L, He L, Lugano R, Roodakker K, Bergqvist M, Smits A, et al. . Idh mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas. Neuro-Oncology (2018) 20(11):1505–16. doi: 10.1093/neuonc/noy088 PubMed DOI PMC

Xiang X, Liu Z, Zhang C, Li Z, Gao J, Zhang C, et al. . Idh mutation subgroup status associates with intratumor heterogeneity and the tumor microenvironment in intrahepatic cholangiocarcinoma. Adv Sci (2021) 8(17):2101230. doi: 10.1002/advs.202101230 PubMed DOI PMC

Chuntova P, Yamamichi A, Chen T, Narayanaswamy R, Ronseaux S, Hudson C, et al. . Inhibition of d-2hg leads to upregulation of a proinflammatory gene signature in a novel hla-A2/Hla-Dr1 transgenic mouse model of Idh1r132h-expressing glioma. J ImmunoTher Cancer (2022) 10(5):e004644. doi: 10.1136/jitc-2022-004644 PubMed DOI PMC

Kohanbash G, Carrera DA, Shrivastav S, Ahn BJ, Jahan N, Mazor T, et al. . Isocitrate dehydrogenase mutations suppress Stat1 and Cd8+ T cell accumulation in gliomas. J Clin Invest (2017) 127(4):1425–37. doi: 10.1172/jci90644 PubMed DOI PMC

Venteicher AS, Tirosh I, Hebert C, Yizhak K, Neftel C, Filbin MG, et al. . Decoupling genetics, lineages, and microenvironment in idh-mutant gliomas by single-cell rna-seq. Science (2017) 355(6332):eaai8478. doi: 10.1126/science.aai8478 PubMed DOI PMC

Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: Glutamine metabolism to cancer therapy. Nat Rev Cancer (2016) 16(10):619–34. doi: 10.1038/nrc.2016.71 PubMed DOI PMC

Yang C, Ko B, Hensley CT, Jiang L, Ajla T, Wasti, et al. . Glutamine oxidation maintains the tca cycle and cell survival during impaired mitochondrial pyruvate transport. (2014) 56(3):414–24. doi: 10.1016/j.molcel.2014.09.025 PubMed DOI PMC

Sappington DR, Siegel ER, Hiatt G, Desai A, Penney RB, Jamshidi-Parsian A, et al. . Glutamine drives glutathione synthesis and contributes to radiation sensitivity of A549 and H460 lung cancer cell lines. Biochim Biophys Acta (BBA) - Gen Subj (2016) 1860(4):836–43. doi: 10.1016/j.bbagen.2016.01.021 PubMed DOI PMC

Ahluwalia GS, Grem JL, Hao Z, Cooney DA. Metabolism and action of amino acid analog anti-cancer agents. Pharmacol Ther (1990) 46(2):243–71. doi: 10.1016/0163-7258(90)90094-i PubMed DOI

Rais R, Jančařík A, Tenora L, Nedelcovych M, Alt J, Englert J, et al. . Discovery of 6-Diazo-5-Oxo-L-Norleucine (Don) prodrugs with enhanced csf delivery in monkeys: A potential treatment for glioblastoma. J Med Chem (2016) 59(18):8621–33. doi: 10.1021/acs.jmedchem.6b01069 PubMed DOI

Oh M-H, Sun I-H, Zhao L, Leone RD, Sun I-M, Xu W, et al. . Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J Clin Invest (2020) 130(7):3865–84. doi: 10.1172/jci131859 PubMed DOI PMC

Leone RD, Zhao L, Englert JM, Sun I-M, Oh M-H, Sun I-H, et al. . Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science (2019) 366(6468):1013–21. doi: 10.1126/science.aav2588 PubMed DOI PMC

Yang L, Achreja A, Yeung T-L, Mangala Lingegowda S, Jiang D, Han C, et al. . Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metab (2016) 24(5):685–700. doi: 10.1016/j.cmet.2016.10.011 PubMed DOI PMC

Edwards DN, Ngwa VM, Raybuck AL, Wang S, Hwang Y, Kim LC, et al. . Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J Clin Invest (2021) 131(4):e140100. doi: 10.1172/jci140100 PubMed DOI PMC

Schulte ML, Fu A, Zhao P, Li J, Geng L, Smith ST, et al. . Pharmacological blockade of Asct2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med (2018) 24(2):194–202. doi: 10.1038/nm.4464 PubMed DOI PMC

Xiang Y, Stine ZE, Xia J, Lu Y, O’Connor RS, Altman BJ, et al. . Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis. J Clin Invest (2015) 125(6):2293–306. doi: 10.1172/jci75836 PubMed DOI PMC

Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, et al. . Antitumor activity of the glutaminase inhibitor cb-839 in triple-negative breast cancer. Mol Cancer Ther (2014) 13(4):890–901. doi: 10.1158/1535-7163.mct-13-0870 PubMed DOI

Robinson M,M, Mcbryant J,S, Tsukamoto T, Rojas C, Ferraris V,D, Hamilton K,S, et al. . Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-Phenylacetamido-1,2,4-Thiadiazol-2-Yl)Ethyl sulfide (Bptes). Biochem J (2007) 406(3):407–14. doi: 10.1042/bj20070039 PubMed DOI PMC

Jin H, Wang S, Zaal EA, Wang C, Wu H, Bosma A, et al. . A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer. eLife (2020) 9:e56749. doi: 10.7554/elife.56749 PubMed DOI PMC

Varghese S, Pramanik S, Williams LJ, Hodges HR, Hudgens CW, Fischer GM, et al. . The glutaminase inhibitor cb-839 (Telaglenastat) enhances the antimelanoma activity of T-Cell–mediated immunotherapies. Mol Cancer Ther (2021) 20(3):500–11. doi: 10.1158/1535-7163.mct-20-0430 PubMed DOI PMC

Best SA, Gubser PM, Sethumadhavan S, Kersbergen A, Negrón Abril YL, Goldford J, et al. . Glutaminase inhibition impairs Cd8 T cell activation in Stk11-/Lkb1-Deficient lung cancer. Cell Metab (2022) 34(6):874–87.e6. doi: 10.1016/j.cmet.2022.04.003 PubMed DOI

Huang H, Vandekeere S, Kalucka J, Bierhansl L, Zecchin A, Brüning U, et al. . Role of glutamine and interlinked asparagine metabolism in vessel formation. EMBO J (2017) 36(16):2334–52. doi: 10.15252/embj.201695518 PubMed DOI PMC

Le A, Lane N,A, Hamaker M, Bose S, Gouw A, Barbi J, et al. . Glucose-independent glutamine metabolism Via tca cycling for proliferation and survival in b cells. Cell Metab (2012) 15(1):110–21. doi: 10.1016/j.cmet.2011.12.009 PubMed DOI PMC

Byun J-K, Park M, Lee S, Yun JW, Lee J, Kim JS, et al. . Inhibition of glutamine utilization synergizes with immune checkpoint inhibitor to promote antitumor immunity. Mol Cell (2020) 80(4):592–606.e8. doi: 10.1016/j.molcel.2020.10.015 PubMed DOI

Elgogary A, Xu Q, Poore B, Alt J, Zimmermann SC, Zhao L, et al. . Combination therapy with bptes nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer. Proc Natl Acad Sci (2016) 113(36):E5328–E36. doi: 10.1073/pnas.1611406113 PubMed DOI PMC

Eelen G, Dubois C, Cantelmo AR, Goveia J, Brüning U, Deran M, et al. . Role of glutamine synthetase in angiogenesis beyond glutamine synthesis. Nature (2018) 561(7721):63–9. doi: 10.1038/s41586-018-0466-7 PubMed DOI

Palmieri EM, Menga A, Martín-Pérez R, Quinto A, Riera-Domingo C, De Tullio G, et al. . Pharmacologic or genetic targeting of glutamine synthetase skews macrophages toward an M1-like phenotype and inhibits tumor metastasis. Cell Rep (2017) 20(7):1654–66. doi: 10.1016/j.celrep.2017.07.054 PubMed DOI PMC

Stine ZE, Schug ZT, Salvino JM, Dang CV. Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discovery (2022) 21(2):141–62. doi: 10.1038/s41573-021-00339-6 PubMed DOI PMC

Kidd JG. Regression of transplanted lymphomas induced in vivo by means of normal Guinea pig serum. J Exp Med (1953) 98(6):583–606. doi: 10.1084/jem.98.6.583 PubMed DOI PMC

Broome JD. Evidence that the l-asparaginase of Guinea pig serum is responsible for its antilymphoma effects. J Exp Med (1963) 118(1):121–48. doi: 10.1084/jem.118.1.121 PubMed DOI PMC

Chiu M, Taurino G, Bianchi MG, Kilberg MS, Bussolati O. Asparagine synthetase in cancer: Beyond acute lymphoblastic leukemia. Front Oncol (2019) 9:1480. doi: 10.3389/fonc.2019.01480 PubMed DOI PMC

Maxwell M, McCoy TA, Neuman RE. The amino acid requirements of the walker carcinosarcoma 256 in vitro. Cancer Res (1956) 16(10 Part 1):979–84. PubMed

Wu J, Li G, Li L, Li D, Dong Z, Jiang P. Asparagine enhances lck signalling to potentiate Cd8+ T-cell activation and anti-tumour responses. Nat Cell Biol (2021) 23(1):75–86. doi: 10.1038/s41556-020-00615-4 PubMed DOI

Alexandrou C, Al-Aqbi SS, Higgins JA, Boyle W, Karmokar A, Andreadi C, et al. . Sensitivity of colorectal cancer to arginine deprivation therapy is shaped by differential expression of urea cycle enzymes. Sci Rep (2018) 8(1):12096. doi: 10.1038/s41598-018-30591-7 PubMed DOI PMC

Albaugh VL, Pinzon-Guzman C, Barbul A. Arginine-dual roles as an onconutrient and immunonutrient. J Surg Oncol (2017) 115(3):273–80. doi: 10.1002/jso.24490 PubMed DOI PMC

Mussai F, Egan S, Higginbotham-Jones J, Perry T, Beggs A, Odintsova E, et al. . Arginine dependence of acute myeloid leukemia blast proliferation: A novel therapeutic target. Blood (2015) 125(15):2386–96. doi: 10.1182/blood-2014-09-600643 PubMed DOI PMC

Fultang L, Booth S, Yogev O, Martins Da Costa B, Tubb V, Panetti S, et al. . Metabolic engineering against the arginine microenvironment enhances car-T cell proliferation and therapeutic activity. Blood (2020) 136(10):1155–60. doi: 10.1182/blood.2019004500 PubMed DOI PMC

Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, et al. . L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell (2016) 167(3):829–42.e13. doi: 10.1016/j.cell.2016.09.031 PubMed DOI PMC

Canale FP, Basso C, Antonini G, Perotti M, Li N, Sokolovska A, et al. . Metabolic modulation of tumours with engineered bacteria for immunotherapy. Nature (2021) 598(7882):662–6. doi: 10.1038/s41586-021-04003-2 PubMed DOI

Kaiser P. Methionine dependence of cancer. Biomolecules (2020) 10(4):568. doi: 10.3390/biom10040568 PubMed DOI PMC

Sanderson SM, Gao X, Dai Z, Locasale JW. Methionine metabolism in health and cancer: A nexus of diet and precision medicine. Nat Rev Cancer (2019) 19(11):625–37. doi: 10.1038/s41568-019-0187-8 PubMed DOI

Hoffman RM, Tan Y, Li S, Han Q, Zavala J, Zavala J, Jr. Pilot phase I clinical trial of methioninase on high-stage cancer patients: Rapid depletion of circulating methionine. Methods Mol Biol (2019) 1866:231–42 doi: 10.1007/978-1-4939-8796-2_17 PubMed DOI

Hung MH, Lee JS, Ma C, Diggs LP, Heinrich S, Chang CW, et al. . Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma. Nat Commun (2021) 12(1):1455. doi: 10.1038/s41467-021-21804-1 PubMed DOI PMC

Bian Y, Li W, Kremer DM, Sajjakulnukit P, Li S, Crespo J, et al. . Cancer Slc43a2 alters T cell methionine metabolism and histone methylation. Nature (2020) 585(7824):277–82. doi: 10.1038/s41586-020-2682-1 PubMed DOI PMC

Burke L, Guterman I, Palacios Gallego R, Britton RG, Burschowsky D, Tufarelli C, et al. . The janus-like role of proline metabolism in cancer. Cell Death Discovery (2020) 6:104. doi: 10.1038/s41420-020-00341-8 PubMed DOI PMC

Loayza-Puch F, Rooijers K, Buil LCM, Zijlstra J, F. Oude Vrielink J, Lopes R, et al. . Tumour-specific proline vulnerability uncovered by differential ribosome codon reading. Nature (2016) 530(7591):490–4. doi: 10.1038/nature16982 PubMed DOI

Westbrook RL, Bridges E, Roberts J, Escribano-Gonzalez C, Eales KL, Vettore LA, et al. . Proline synthesis through Pycr1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions. Cell Rep (2022) 38(5):110320. doi: 10.1016/j.celrep.2022.110320 PubMed DOI PMC

Liu Y, Mao C, Wang M, Liu N, Ouyang L, Liu S, et al. . Cancer progression is mediated by proline catabolism in non-small cell lung cancer. Oncogene (2020) 39(11):2358–76. doi: 10.1038/s41388-019-1151-5 PubMed DOI

Elia I, Broekaert D, Christen S, Boon R, Radaelli E, Orth MF, et al. . Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells. Nat Commun (2017) 8(1):15267. doi: 10.1038/ncomms15267 PubMed DOI PMC

Bai J, Liu T, Tu B, Yuan M, Shu Z, Fan M, et al. . Autophagy loss impedes cancer-associated fibroblast activation via downregulating proline biosynthesis. Autophagy (2022) 1-12. doi: 10.1080/15548627.2022.2093026 PubMed DOI PMC

Milne K, Sun J, Zaal EA, Mowat J, Celie PHN, Fish A, et al. . A fragment-like approach to Pycr1 inhibition. Bioorg Med Chem Lett (2019) 29(18):2626–31. doi: 10.1016/j.bmcl.2019.07.047 PubMed DOI

Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogenesis (2016) 5:e189. doi: 10.1038/oncsis.2015.49 PubMed DOI PMC

Zaugg K, Yao Y, Reilly PT, Kannan K, Kiarash R, Mason J, et al. . Carnitine palmitoyltransferase 1c promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev (2011) 25(10):1041–51. doi: 10.1101/gad.1987211 PubMed DOI PMC

Schcolnik-Cabrera A, Chavez-Blanco A, Dominguez-Gomez G, Taja-Chayeb L, Morales-Barcenas R, Trejo-Becerril C, et al. . Orlistat as a fasn inhibitor and multitargeted agent for cancer therapy. Expert Opin Investig Drugs (2018) 27(5):475–89. doi: 10.1080/13543784.2018.1471132 PubMed DOI

Murata S, Yanagisawa K, Fukunaga K, Oda T, Kobayashi A, Sasaki R, et al. . Fatty acid synthase inhibitor cerulenin suppresses liver metastasis of colon cancer in mice. Cancer Sci (2010) 101(8):1861–5. doi: 10.1111/j.1349-7006.2010.01596.x PubMed DOI PMC

Alli PM, Pinn ML, Jaffee EM, McFadden JM, Kuhajda FP. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-n transgenic mice. Oncogene (2005) 24(1):39–46. doi: 10.1038/sj.onc.1208174 PubMed DOI

Li S, Qiu L, Wu B, Shen H, Zhu J, Zhou L, et al. . Tofa suppresses ovarian cancer cell growth in vitro and in vivo. Mol Med Rep (2013) 8(2):373–8. doi: 10.3892/mmr.2013.1505 PubMed DOI

Schlaepfer IR, Rider L, Rodrigues LU, Gijon MA, Pac CT, Romero L, et al. . Lipid catabolism Via Cpt1 as a therapeutic target for prostate cancer. Mol Cancer Ther (2014) 13(10):2361–71. doi: 10.1158/1535-7163.MCT-14-0183 PubMed DOI PMC

Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, et al. . Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest (2010) 120(1):142–56. doi: 10.1172/JCI38942 PubMed DOI PMC

Holubarsch CJ, Rohrbach M, Karrasch M, Boehm E, Polonski L, Ponikowski P, et al. . A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: The ergo (Etomoxir for the recovery of glucose oxidation) study. Clin Sci (Lond) (2007) 113(4):205–12. doi: 10.1042/CS20060307 PubMed DOI

Pacilli A, Calienni M, Margarucci S, D'Apolito M, Petillo O, Rocchi L, et al. . Carnitine-acyltransferase system inhibition, cancer cell death, and prevention of myc-induced lymphomagenesis. J Natl Cancer Inst (2013) 105(7):489–98. doi: 10.1093/jnci/djt030 PubMed DOI

McKelvey KJ, Wilson EB, Short S, Melcher AA, Biggs M, Diakos CI, et al. . Glycolysis and fatty acid oxidation inhibition improves survival in glioblastoma. Front Oncol (2021) 11:633210. doi: 10.3389/fonc.2021.633210 PubMed DOI PMC

Lopes-Coelho F, Andre S, Felix A, Serpa J. Breast cancer metabolic cross-talk: Fibroblasts are hubs and breast cancer cells are gatherers of lipids. Mol Cell Endocrinol (2018) 462(Pt B):93–106. doi: 10.1016/j.mce.2017.01.031 PubMed DOI

Santi A, Caselli A, Ranaldi F, Paoli P, Mugnaioni C, Michelucci E, et al. . Cancer associated fibroblasts transfer lipids and proteins to cancer cells through cargo vesicles supporting tumor growth. Biochim Biophys Acta (2015) 1853(12):3211–23. doi: 10.1016/j.bbamcr.2015.09.013 PubMed DOI

Gong J, Lin Y, Zhang H, Liu C, Cheng Z, Yang X, et al. . Reprogramming of lipid metabolism in cancer-associated fibroblasts potentiates migration of colorectal cancer cells. Cell Death Dis (2020) 11(4):267. doi: 10.1038/s41419-020-2434-z PubMed DOI PMC

Peng S, Chen D, Cai J, Yuan Z, Huang B, Li Y, et al. . Enhancing cancer-associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis. Mol Oncol (2021) 15(5):1391–411. doi: 10.1002/1878-0261.12917 PubMed DOI PMC

Schoors S, Bruning U, Missiaen R, Queiroz KC, Borgers G, Elia I, et al. . Fatty acid carbon is essential for dntp synthesis in endothelial cells. Nature (2015) 520(7546):192–7. doi: 10.1038/nature14362 PubMed DOI PMC

Wong BW, Wang X, Zecchin A, Thienpont B, Cornelissen I, Kalucka J, et al. . The role of fatty acid beta-oxidation in lymphangiogenesis. Nature (2017) 542(7639):49–54. doi: 10.1038/nature21028 PubMed DOI

Patella F, Schug ZT, Persi E, Neilson LJ, Erami Z, Avanzato D, et al. . Proteomics-based metabolic modeling reveals that fatty acid oxidation (Fao) controls endothelial cell (Ec) permeability. Mol Cell Proteomics (2015) 14(3):621–34. doi: 10.1074/mcp.M114.045575 PubMed DOI PMC

Kalucka J, Bierhansl L, Conchinha NV, Missiaen R, Elia I, Bruning U, et al. . Quiescent endothelial cells upregulate fatty acid beta-oxidation for vasculoprotection Via redox homeostasis. Cell Metab (2018) 28(6):881–94 e13. doi: 10.1016/j.cmet.2018.07.016 PubMed DOI

Wei X, Schneider JG, Shenouda SM, Lee A, Towler DA, Chakravarthy MV, et al. . De novo lipogenesis maintains vascular homeostasis through endothelial nitric-oxide synthase (Enos) palmitoylation. J Biol Chem (2011) 286(4):2933–45. doi: 10.1074/jbc.M110.193037 PubMed DOI PMC

Seguin F, Carvalho MA, Bastos DC, Agostini M, Zecchin KG, Alvarez-Flores MP, et al. . The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas. Br J Cancer (2012) 107(6):977–87. doi: 10.1038/bjc.2012.355 PubMed DOI PMC

Browne CD, Hindmarsh EJ, Smith JW. Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor. FASEB J (2006) 20(12):2027–35. doi: 10.1096/fj.05-5404com PubMed DOI

Biswas SK, Mantovani A. Orchestration of metabolism by macrophages. Cell Metab (2012) 15(4):432–7. doi: 10.1016/j.cmet.2011.11.013 PubMed DOI

Namgaladze D, Lips S, Leiker TJ, Murphy RC, Ekroos K, Ferreiros N, et al. . Inhibition of macrophage fatty acid beta-oxidation exacerbates palmitate-induced inflammatory and endoplasmic reticulum stress responses. Diabetologia (2014) 57(5):1067–77. doi: 10.1007/s00125-014-3173-4 PubMed DOI

Xiu F, Diao L, Qi P, Catapano M, Jeschke MG. Palmitate differentially regulates the polarization of differentiating and differentiated macrophages. Immunology (2016) 147(1):82–96. doi: 10.1111/imm.12543 PubMed DOI PMC

Wu H, Han Y, Rodriguez Sillke Y, Deng H, Siddiqui S, Treese C, et al. . Lipid droplet-dependent fatty acid metabolism controls the immune suppressive phenotype of tumor-associated macrophages. EMBO Mol Med (2019) 11(11):e10698. doi: 10.15252/emmm.201910698 PubMed DOI PMC

Bose D, Banerjee S, Chatterjee N, Das S, Saha M, Saha KD. Inhibition of tgf-beta induced lipid droplets switches M2 macrophages to M1 phenotype. Toxicol In Vitro (2019) 58:207–14. doi: 10.1016/j.tiv.2019.03.037 PubMed DOI

Schumann T, Adhikary T, Wortmann A, Finkernagel F, Lieber S, Schnitzer E, et al. . Deregulation of Pparbeta/Delta target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment. Oncotarget (2015) 6(15):13416–33. doi: 10.18632/oncotarget.3826 PubMed DOI PMC

Corn KC, Windham MA, Rafat M. Lipids in the tumor microenvironment: From cancer progression to treatment. Prog Lipid Res (2020) 80:101055. doi: 10.1016/j.plipres.2020.101055 PubMed DOI PMC

Kurniawan H, Soriano-Baguet L, Brenner D. Regulatory T cell metabolism at the intersection between autoimmune diseases and cancer. Eur J Immunol (2020) 50(11):1626–42. doi: 10.1002/eji.201948470 PubMed DOI PMC

Kleinfeld AM, Okada C. Free fatty acid release from human breast cancer tissue inhibits cytotoxic T-Lymphocyte-Mediated killing. J Lipid Res (2005) 46(9):1983–90. doi: 10.1194/jlr.M500151-JLR200 PubMed DOI

Miska J, Lee-Chang C, Rashidi A, Muroski ME, Chang AL, Lopez-Rosas A, et al. . Hif-1alpha is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep (2019) 27(1):226–37 e4. doi: 10.1016/j.celrep.2019.03.029 PubMed DOI PMC

Zhang C, Yue C, Herrmann A, Song J, Egelston C, Wang T, et al. . Stat3 activation-induced fatty acid oxidation in Cd8(+) T effector cells is critical for obesity-promoted breast tumor growth. Cell Metab (2020) 31(1):148–61 e5. doi: 10.1016/j.cmet.2019.10.013 PubMed DOI PMC

Chowdhury PS, Chamoto K, Kumar A, Honjo T. 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 (2018) 6(11):1375–87. doi: 10.1158/2326-6066.CIR-18-0095 PubMed DOI

Herber DL, Cao W, Nefedova Y, Novitskiy SV, Nagaraj S, Tyurin VA, et al. . Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med (2010) 16(8):880–6. doi: 10.1038/nm.2172 PubMed DOI PMC

de Almeida LY, Mariano FS, Bastos DC, Cavassani KA, Raphelson J, Mariano VS, et al. . The antimetastatic activity of orlistat is accompanied by an antitumoral immune response in mouse melanoma. Cancer Chemother Pharmacol (2020) 85(2):321–30. doi: 10.1007/s00280-019-04010-1 PubMed DOI

DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv (2016) 2(5):e1600200. doi: 10.1126/sciadv.1600200 PubMed DOI PMC

Wang W, Cui J, Ma H, Lu W, Huang J. Targeting pyrimidine metabolism in the era of precision cancer medicine. Front Oncol (2021) 11:684961. doi: 10.3389/fonc.2021.684961 PubMed DOI PMC

Ogrodzinski MP, Teoh ST, Lunt SY. Targeting subtype-specific metabolic preferences in nucleotide biosynthesis inhibits tumor growth in a breast cancer model. Cancer Res (2021) 81(2):303–14. doi: 10.1158/0008-5472.can-20-1666 PubMed DOI

Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-Aminopteroyl-Glutamic acid (Aminopterin). New Engl J Med (1948) 238(23):787–93. doi: 10.1056/nejm194806032382301 PubMed DOI

Walling J. From methotrexate to pemetrexed and beyond. a review of the pharmacodynamic and clinical properties of antifolates. Investigat New Drugs (2006) 24(1):37–77. doi: 10.1007/s10637-005-4541-1 PubMed DOI

Luengo A, Gui DY, Vander Heiden MG. Targeting metabolism for cancer therapy. Cell Chem Biol (2017) 24(9):1161–80. doi: 10.1016/j.chembiol.2017.08.028 PubMed DOI PMC

An Q, Robins P, Lindahl T, Barnes DE. 5-fluorouracil incorporated into DNA is excised by the Smug1 DNA glycosylase to reduce drug cytotoxicity. Cancer Res (2007) 67(3):940–5. doi: 10.1158/0008-5472.can-06-2960 PubMed DOI

Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V. Gemcitabine: Metabolism, mechanisms of action, and self-potentiation. Semin Oncol (1995) 22(4 Suppl 11):3–10. PubMed

Boukalova S, Hubackova S, Milosevic M, Ezrova Z, Neuzil J, Rohlena J. Dihydroorotate dehydrogenase in oxidative phosphorylation and cancer. Biochim Biophys Acta Mol Basis Dis (2020) 1866(6):165759. doi: 10.1016/j.bbadis.2020.165759 PubMed DOI

Zhou Y, Tao L, Zhou X, Zuo Z, Gong J, Liu X, et al. . Dhodh and cancer: Promising prospects to be explored. Cancer Metab (2021) 9(1):22. doi: 10.1186/s40170-021-00250-z PubMed DOI PMC

Li L, Ng SR, Colon CI, Drapkin BJ, Hsu PP, Li Z, et al. . Identification of dhodh as a therapeutic target in small cell lung cancer. Sci Transl Med (2019) 11(517):eaaw7852. doi: 10.1126/scitranslmed.aaw7852 PubMed DOI PMC

Mathur D, Stratikopoulos E, Ozturk S, Steinbach N, Pegno S, Schoenfeld S, et al. . Pten regulates glutamine flux to pyrimidine synthesis and sensitivity to dihydroorotate dehydrogenase inhibition. Cancer Discovery (2017) 7(4):380–90. doi: 10.1158/2159-8290.CD-16-0612 PubMed DOI PMC

Koundinya M, Sudhalter J, Courjaud A, Lionne B, Touyer G, Bonnet L, et al. . Dependence on the pyrimidine biosynthetic enzyme dhodh is a synthetic lethal vulnerability in mutant kras-driven cancers. Cell Chem Biol (2018) 25(6):705–17.e11. doi: 10.1016/j.chembiol.2018.03.005 PubMed DOI

Walter M, Herr P. Re-discovery of pyrimidine salvage as target in cancer therapy. Cells (2022) 11(4):739. doi: 10.3390/cells11040739 PubMed DOI PMC

Cuthbertson CR, Guo H, Kyani A, Madak JT, Arabzada Z, Neamati N. The dihydroorotate dehydrogenase inhibitor brequinar is synergistic with Ent1/2 inhibitors. ACS Pharmacol Trans Sci (2020) 3(6):1242–52. doi: 10.1021/acsptsci.0c00124 PubMed DOI PMC

Peters GJ, Schwartsmann G, Nadal JC, Laurensse EJ, van Groeningen CJ, van der Vijgh WJ, et al. . In vivo inhibition of the pyrimidine De novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (Dup-785; nsc 368390) in mice and patients. Cancer Res (1990) 50(15):4644–9. PubMed

Dey P, Kimmelman AC, DePinho RA. Metabolic codependencies in the tumor microenvironment. Cancer Discovery (2021) 11(5):1067–81. doi: 10.1158/2159-8290.CD-20-1211 PubMed DOI PMC

Rohlenova K, Goveia J, Garcia-Caballero M, Subramanian A, Kalucka J, Treps L, et al. . Single-cell rna sequencing maps endothelial metabolic plasticity in pathological angiogenesis. Cell Metab (2020) 31(4):862–77 e14. doi: 10.1016/j.cmet.2020.03.009 PubMed DOI

Basaki Y, Chikahisa L, Aoyagi K, Miyadera K, Yonekura K, Hashimoto A, et al. . Gamma-hydroxybutyric acid and 5-fluorouracil, metabolites of uft, inhibit the angiogenesis induced by vascular endothelial growth factor. Angiogenesis (2001) 4(3):163–73. doi: 10.1023/a:1014059528046 PubMed DOI

Yonekura K, Basaki Y, Chikahisa L, Okabe S, Hashimoto A, Miyadera K, et al. . Uft and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin Cancer Res (1999) 5(8):2185–91. PubMed

Presta M, Belleri M, Vacca A, Ribatti D. Anti-angiogenic activity of the purine analog 6-thioguanine. Leukemia (2002) 16(8):1490–9. doi: 10.1038/sj.leu.2402646 PubMed DOI

Wang C, Xi W, Jiang J, Ji J, Yu Y, Zhu Z, et al. . Metronomic chemotherapy remodel cancer-associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice. Oncol Lett (2017) 14(6):7903–9. doi: 10.3892/ol.2017.7197 PubMed DOI PMC

Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A, et al. . Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by il-17a. J Exp Med (2013) 210(13):2851–72. doi: 10.1084/jem.20131195 PubMed DOI PMC

Quéméneur L, Gerland L-M, Flacher M, Ffrench M, Revillard J-P, Genestier L. Differential control of cell cycle, proliferation, and survival of primary T lymphocytes by purine and pyrimidine nucleotides. J Immunol (2003) 170(10):4986–95. doi: 10.4049/jimmunol.170.10.4986 PubMed DOI

Peeters MJW, Aehnlich P, Pizzella A, Mølgaard K, Seremet T, Met Ö, et al. . Mitochondrial-linked De novo pyrimidine biosynthesis dictates human T-cell proliferation but not expression of effector molecules. Front Immunol (2021) 12:718863. doi: 10.3389/fimmu.2021.718863 PubMed DOI PMC

Siemasko KF, Chong ASF, Williams JW, Bremer EG, Finnegan A. Regulation of b cell function by the immunosuppressive agent Leflunomide1. Transplantation (1996) 61(4):635–42. doi: 10.1097/00007890-199602270-00020 PubMed DOI

Ringshausen I, Oelsner M, Bogner C, Peschel C, Decker T. The immunomodulatory drug leflunomide inhibits cell cycle progression of b-cll cells. Leukemia (2008) 22(3):635–8. doi: 10.1038/sj.leu.2404922 PubMed DOI

Chong AS, Finnegan A, Jiang X, Gebel H, Sankary HN, Foster P, et al. . Leflunomide, a novel immunosuppressive agent. the mechanism of inhibition of T cell proliferation. Transplantation (1993) 55(6):1361–6. doi: 10.1097/00007890-199306000-00028 PubMed DOI

Read SW, DeGrezia M, Ciccone EJ, DerSimonian R, Higgins J, Adelsberger JW, et al. . The effect of leflunomide on cycling and activation of T-cells in hiv-1-Infected participants. PloS One (2010) 5(8):e11937. doi: 10.1371/journal.pone.0011937 PubMed DOI PMC

Pinschewer DD, Ochsenbein AF, Fehr T, Zinkernagel RM. Leflunomide-mediated suppression of antiviral antibody and T cell responses: Differential restoration by Uridine1. Transplantation (2001) 72(4):712–9. doi: 10.1097/00007890-200108270-00026 PubMed DOI

Aly L, Hemmer B, Korn T. From leflunomide to teriflunomide: Drug development and immunosuppressive oral drugs in the treatment of multiple sclerosis. Curr Neuropharmacol (2017) 15(6):874–91. doi: 10.2174/1570159X14666161208151525 PubMed DOI PMC

Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, et al. . 5-fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res (2010) 70(8):3052–61. doi: 10.1158/0008-5472.CAN-09-3690 PubMed DOI

Tian J, Zhang D, Kurbatov V, Wang Q, Wang Y, Fang D, et al. . 5-fluorouracil efficacy requires anti-tumor immunity triggered by cancer-Cell-Intrinsic sting. EMBO J (2021) 40(7):e106065. doi: 10.15252/embj.2020106065 PubMed DOI PMC

Wu Y, Deng Z, Wang H, Ma W, Zhou C, Zhang S. Repeated cycles of 5-fluorouracil chemotherapy impaired anti-tumor functions of cytotoxic T cells in a Ct26 tumor-bearing mouse model. BMC Immunol (2016) 17(1):29. doi: 10.1186/s12865-016-0167-7 PubMed DOI PMC

Yusung S, McGovern D, Lin L, Hommes D, Lagishetty V, Braun J. Nk cells are biologic and biochemical targets of 6-mercaptopurine in crohn's disease patients. Clin Immunol (2017) 175:82–90. doi: 10.1016/j.clim.2016.12.004 PubMed DOI PMC

McCarthy MT, Moncayo G, Hiron TK, Jakobsen NA, Valli A, Soga T, et al. . Purine nucleotide metabolism regulates expression of the human immune ligand mica. J Biol Chem (2018) 293(11):3913–24. doi: 10.1074/jbc.m117.809459 PubMed DOI PMC

Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol (2008) 8(1):59–73. doi: 10.1038/nri2216 PubMed DOI

Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic gr-1+/Cd11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res (2005) 11(18):6713–21. doi: 10.1158/1078-0432.ccr-05-0883 PubMed DOI

Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD. Gemcitabine directly inhibits myeloid derived suppressor cells in Balb/C mice bearing 4t1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharmacol (2009) 9(7-8):900–9. doi: 10.1016/j.intimp.2009.03.015 PubMed DOI

Coelho AR, Oliveira PJ. Dihydroorotate dehydrogenase inhibitors in sars-Cov-2 infection. Eur J Clin Invest (2020) 50(10):e13366. doi: 10.1111/eci.13366 PubMed DOI PMC

Sprenger H-G, Macvicar T, Bahat A, Fiedler KU, Hermans S, Ehrentraut D, et al. . Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity. Nat Metab (2021) 3(5):636–50. doi: 10.1038/s42255-021-00385-9 PubMed DOI PMC

Lu C-S, Lin C-W, Chang Y-H, Chen H-Y, Chung W-C, Lai W-Y, et al. . Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy. J ImmunoTher Cancer (2020) 8(2):e001392. doi: 10.1136/jitc-2020-001392 PubMed DOI PMC

Lemberg KM, Gori SS, Tsukamoto T, Rais R, Slusher BS. Clinical development of metabolic inhibitors for oncology. J Clin Invest (2022) 132(1):e148550. doi: 10.1172/JCI148550 PubMed DOI PMC