Cancer cells rely on certain extracellular nutrients to sustain their metabolism and growth. Solute carrier (SLC) transporters enable cells to acquire extracellular nutrients or shuttle intracellular nutrients across organelles. However, the function of many SLC transporters in cancer is unknown. Determining the key SLC transporters promoting cancer growth could reveal important therapeutic opportunities. Here we summarize recent findings and knowledge gaps on SLC transporters in cancer. We highlight existing inhibitors for studying these transporters, clinical trials on treating cancer by blocking transporters, and compensatory transporters used by cancer cells to evade treatment. We propose targeting transporters simultaneously or in combination with targeted therapy or immunotherapy as alternative strategies for effective cancer therapy.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23:27–47.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.
Warburg O. On the origin of cancer cells. Science. 1956;123:309–14.
Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer. 2013;13:572–83.
Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013;496:101–5.
Sousa CM, Biancur DE, Wang X, Halbrook CJ, Sherman MH, Zhang L, et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature. 2016;536:479–83.
Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16:619–34.
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.
Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T, van den Broek NJF, et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature. 2017;544:372–6.
Gao X, Sanderson SM, Dai Z, Reid MA, Cooper DE, Lu M, et al. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature. 2019;572:397–401.
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;585:277–82.
Banh RS, Biancur DE, Yamamoto K, Sohn ASW, Walters B, Kuljanin M, et al. Neurons release serine to support mRNA translation in pancreatic cancer. Cell. 2020;183:1202–18.e25.
Muthusamy T, Cordes T, Handzlik MK, You L, Lim EW, Gengatharan J, et al. Serine restriction alters sphingolipid diversity to constrain tumour growth. Nature. 2020;586:790–5.
Nwosu ZC, Piorońska W, Battello N, Zimmer AD, Dewidar B, Han M, et al. Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance. EBioMedicine. 2020;54:102699.
Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Trimmer C, et al. The autophagic tumor stroma model of cancer or “battery-operated tumor growth”: a simple solution to the autophagy paradox. Cell Cycle. 2010;9:4297–306.
Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013;497:633–7.
Kamphorst JJ, Nofal M, Commisso C, Hackett SR, Lu W, Grabocka E, et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 2015;75:544–53.
Reckzeh ES, Waldmann H. Small‐molecule inhibition of glucose transporters GLUT‐1–4. ChemBioChem. 2020;21:45–52.
Adams DJ, Ito D, Rees MG, Seashore-Ludlow B, Puyang X, Ramos AH, et al. NAMPT Is the cellular target of STF-31-like small-molecule probes. ACS Chem Biol. 2014;9:2247–54.
Guo Z, Cheng Z, Wang J, Liu W, Peng H, Wang Y, et al. Discovery of a potent GLUT inhibitor from a library of rapafucins by using 3D microarrays. Angew Chem Int Ed. 2019;58:17158–62.
Shi Y, Liu S, Ahmad S, Gao Q. Targeting key transporters in tumor glycolysis as a novel anticancer strategy. CTMC. 2018;18:454–66.
Gonzalez PS, O’Prey J, Cardaci S, Barthet VJA, Sakamaki J, Beaumatin F, et al. Mannose impairs tumour growth and enhances chemotherapy. Nature 2018;563:719–23.
Nwosu ZC, Megger DA, Hammad S, Sitek B, Roessler S, Ebert MP, et al. Identification of the consistently altered metabolic targets in human hepatocellular carcinoma. Cell Mol Gastroenterol Hepatol. 2017;4:303–323. e1.
Kim YH, Jeong DC, Pak K, Han ME, Kim JY, Liangwen L, et al. SLC2A2 (GLUT2) as a novel prognostic factor for hepatocellular carcinoma. Oncotarget 2017;8:68381–92.
Byrne FL, Olzomer EM, Brink R, Hoehn KL. Knockout of glucose transporter GLUT6 has minimal effects on whole body metabolic physiology in mice. Am J Physiol-Endocrinol Metab. 2018;315:E286–93.
Scafoglio CR, Villegas B, Abdelhady G, Bailey ST, Liu J, Shirali AS, et al. Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma. Sci Transl Med 2018;10:eaat5933.
Scafoglio C, Hirayama BA, Kepe V, Liu J, Ghezzi C, Satyamurthy N, et al. Functional expression of sodium-glucose transporters in cancer. Proc Natl Acad Sci USA 2015;112:E4111–9.
Chen WL, Wang YY, Zhao A, Xia L, Xie G, Su M, et al. Enhanced fructose utilization mediated by SLC2A5 is a unique metabolic feature of acute myeloid leukemia with therapeutic potential. Cancer Cell. 2016;30:779–91.
Chen WL, Jin X, Wang M, Liu D, Luo Q, Tian H, et al. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling. JCI Insight. 2020;5:e131596.
Carreño DV, Corro NB, Cerda-Infante JF, Echeverría CE, Asencio-Barría CA, Torres-Estay VA, et al. Dietary fructose promotes prostate cancer growth. Cancer Res. 2021;81:2824–32.
Taylor SR, Ramsamooj S, Liang RJ, Katti A, Pozovskiy R, Vasan N, et al. Dietary fructose improves intestinal cell survival and nutrient absorption. Nature. 2021;597:263–7.
Goncalves MD, Lu C, Tutnauer J, Hartman TE, Hwang SK, Murphy CJ, et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science. 2019;363:1345–9.
Shen Z, Li Z, Liu Y, Li Y, Feng X, Zhan Y, et al. GLUT5-KHK axis-mediated fructose metabolism drives proliferation and chemotherapy resistance of colorectal cancer. Cancer Lett. 2022;534:215617.
Lin M, Fang Y, Li Z, Li Y, Feng X, Zhan Y, et al. S100P contributes to promoter demethylation and transcriptional activation of SLC2A5 to promote metastasis in colorectal cancer. Br J Cancer. 2021;125:734–47.
George Thompson AM, Ursu O, Babkin P, Iancu CV, Whang A, Oprea TI, et al. Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation. Sci Rep. 2016;6:24240.
Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care. 2001;24:382–91.
Roef MJ, de Meer K, Kalhan SC, Straver H, Berger R, Reijngoud DJ. Gluconeogenesis in humans with induced hyperlactatemia during low-intensity exercise. Am J Physiol Endocrinol Metab. 2003;284:E1162–71.
Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, et al. Lactate metabolism in human lung tumors. Cell 2017;171:358–371. e9
Granlund KL, Tee SS, Vargas HA, Lyashchenko SK, Reznik E, Fine S, et al. Hyperpolarized MRI of human prostate cancer reveals increased lactate with tumor grade driven by monocarboxylate transporter 1. Cell Metab. 2020;31:105–114. e3.
Choi SYC, Xue H, Wu R, Fazli L, Lin D, Collins CC, et al. The MCT4 gene: a novel, potential target for therapy of advanced prostate cancer. Clin Cancer Res. 2016;22:2721–33.
Payen VL, Hsu MY, Rädecke KS, Wyart E, Vazeille T, Bouzin C, et al. Monocarboxylate transporter MCT1 promotes tumor metastasis independently of its activity as a lactate transporter. Cancer Res. 2017;77:5591–601.
Tasdogan A, Faubert B, Ramesh V, Ubellacker JM, Shen B, Solmonson A, et al. Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 2020;577:115–20.
CRUK Rosetta Grand Challenge Consortium, Najumudeen AK, Ceteci F, Fey SK, Hamm G, Steven RT, et al. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer. Nat Genet. 2021;53:16–26.
Bröer A, Gauthier-Coles G, Rahimi F, van Geldermalsen M, Dorsch D, Wegener A, et al. Ablation of the ASCT2 (SLC1A5) gene encoding a neutral amino acid transporter reveals transporter plasticity and redundancy in cancer cells. J Biol Chem. 2019;294:4012–26.
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;24:194–202.
Zhang Z, Liu R, Shuai Y, Huang Y, Jin R, Wang X, et al. ASCT2 (SLC1A5)-dependent glutamine uptake is involved in the progression of head and neck squamous cell carcinoma. Br J Cancer. 2020;122:82–93.
Wang VMY, Ferreira RMM, Almagro J, Evan T, Legrave N, Zaw Thin M, et al. CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth. Nat Cell Biol. 2019;21:1425–35.
Ni F, Yu WM, Li Z, Graham DK, Jin L, Kang S, et al. Critical role of ASCT2-mediated amino acid metabolism in promoting leukaemia development and progression. Nat Metab. 2019;1:390–403.
Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270–4.
Ogiwara H, Takahashi K, Sasaki M, Kuroda T, Yoshida H, Watanabe R, et al. Targeting the vulnerability of glutathione metabolism in ARID1A-deficient cancers. Cancer Cell. 2019;35:177–190. e8
Badgley MA, Kremer DM, Maurer HC, DelGiorno KE, Lee HJ, Purohit V, et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 2020;368:85–9.
Cramer SL, Saha A, Liu J, Tadi S, Tiziani S, Yan W, et al. Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat Med. 2017;23:120–7.
Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al. Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife. 2014;3:e02523.
Zheng J, Sato M, Mishima E, Sato H, Proneth B, Conrad M. Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines. Cell Death Dis. 2021;12:698.
Zhu J, Berisa M, Schwörer S, Qin W, Cross JR, Thompson CB. Transsulfuration activity can support cell growth upon extracellular cysteine limitation. Cell Metab. 2019;30:865–876. e5.
Mayers JR, Torrence ME, Danai LV, Papagiannakopoulos T, Davidson SM, Bauer MR, et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science. 2016;353:1161–5.
Wang W, Zou W. Amino acids and their transporters in T cell immunity and cancer therapy. Molecular Cell. 2020;80:384–95.
Saito Y, Li L, Coyaud E, Luna A, Sander C, Raught B, et al. LLGL2 rescues nutrient stress by promoting leucine uptake in ER+ breast cancer. Nature. 2019;569:275–9.
Cormerais Y, Giuliano S, LeFloch R, Front B, Durivault J, Tambutte E, et al. Genetic disruption of the multifunctional CD98/LAT1 complex demonstrates the key role of essential amino acid transport in the control of mTORC1 and tumor growth. Cancer Res. 2016;76:4481–92.
Maimaiti M, Sakamoto S, Yamada Y, Sugiura M, Rii J, Takeuchi N, et al. Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma. Sci Rep. 2020;10:1292.
Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, Sabatini DM. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell. 2015;162:540–51.
Knott SRV, Wagenblast E, Khan S, Kim SY, Soto M, Wagner M, et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature. 2018;554:378–81.
Werner A, Pieh D, Echchannaoui H, Rupp J, Rajalingam K, Theobald M, et al. Cationic amino acid transporter-1-mediated arginine uptake is essential for chronic lymphocytic leukemia cell proliferation and viability. Front Oncol. 2019;9:1268.
Lowman XH, Hanse EA, Yang Y, Ishak Gabra MB, Tran TQ, Li H, et al. p53 promotes cancer cell adaptation to glutamine deprivation by upregulating Slc7a3 to increase arginine uptake. Cell Rep. 2019;26:3051–3060. e4.
Tajan M, Hock AK, Blagih J, Robertson NA, Labuschagne CF, Kruiswijk F, et al. A Role for p53 in the adaptation to glutamine starvation through the expression of SLC1A3. Cell Metab. 2018;28:721–736. e6.
Sun J, Nagel R, Zaal EA, Ugalde AP, Han R, Proost N, et al. SLC1A3 contributes to L-asparaginase resistance in solid tumors. EMBO J. 2019;38:e102147.
Chiu M, Taurino G, Bianchi MG, Kilberg MS, Bussolati O. Asparagine synthetase in cancer: beyond acute lymphoblastic leukemia. Front Oncol. 2020;9:1480.
Beyer SR, Mallmann RT, Jaenecke I, Habermeier A, Boissel JP, Closs EI. Identification of cysteine residues in human cationic amino acid transporter hCAT-2A that are targets for inhibition by N-Ethylmaleimide. J Biol Chem. 2013;288:30411–9.
Koundouros N, Poulogiannis G. Reprogramming of fatty acid metabolism in cancer. Br J Cancer. 2020;122:4–22.
Watt MJ, Clark AK, Selth LA, Haynes VR, Lister N, Rebello R, et al. Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer. Sci Transl Med. 2019;11:eaau5758.
Zhang M, Di Martino JS, Bowman RL, Campbell NR, Baksh SC, Simon-Vermot T, et al. Adipocyte-derived lipids mediate melanoma progression via FATP proteins. Cancer Disco. 2018;8:1006–25.
Guillaumond F, Bidaut G, Ouaissi M, Servais S, Gouirand V, Olivares O, et al. Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proc Natl Acad Sci USA 2015;112:2473–8.
Alarcón S, Toro M, de los Á, Villarreal C, Melo R, Fernández R, et al. Decreased equilibrative nucleoside transporter 1 (ENT1) activity contributes to the high extracellular adenosine levels in mesenchymal glioblastoma stem-like cells. Cells. 2020;9:1914.
Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 2009;136:187–95.
Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527:525–30.
Chen CF, Hsu EC, Lin KT, Tu PH, Chang HW, Lin CH, et al. Overlapping high-resolution copy number alterations in cancer genomes identified putative cancer genes in hepatocellular carcinoma. Hepatology. 2010;52:1690–701.
Grozio A, Mills KF, Yoshino J, Bruzzone S, Sociali G, Tokizane K, et al. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab. 2019;1:47–57.
Feigin ME, Garvin T, Bailey P, Waddell N, Chang DK, Kelley DR, et al. Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. Nat Genet. 2017;49:825–33.
Luongo TS, Eller JM, Lu MJ, Niere M, Raith F, Perry C, et al. SLC25A51 is a mammalian mitochondrial NAD+ transporter. Nature. 2020;588:174–9.
Kory N, uit de Bos J, van der Rijt S, Jankovic N, Güra M, Arp N, et al. MCART1/SLC25A51 is required for mitochondrial NAD transport. SciAdv. 2020;6:eabe5310.
Yang J, Zhang Z, Zhang Y, Ni X, Zhang G, Cui X. et al. ZIP4 promotes muscle wasting and cachexia in mice with orthotopic pancreatic tumors by stimulating RAB27B-regulated release of extracellular vesicles from cancer cells. Gastroenterology.2019;156:722–34.e6.
Wang G, Biswas AK, Ma W, Kandpal M, Coker C, Grandgenett PM, et al. Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle. Nat Med. 2018;24:770–81.
Hu J, Locasale JW, Bielas JH, O’Sullivan J, Sheahan K, Cantley LC, et al. Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat Biotechnol. 2013;31:522–9.
Bafaro E, Liu Y, Xu Y, Dempski RE. The emerging role of zinc transporters in cellular homeostasis and cancer. Sig Transduct Target Ther. 2017;2:17029.
Barresi V, Valenti G, Spampinato G, Musso N, Castorina S, Rizzarelli E, et al. Transcriptome analysis reveals an altered expression profile of zinc transporters in colorectal cancer. J Cell Biochem. 2018;119:9707–19.
Garrick MD. Human iron transporters. Genes Nutr. 2011;6:45–54.
Wu J, Bao L, Zhang Z, Yi X. Nrf2 induces cisplatin resistance via suppressing the iron export related gene SLC40A1 in ovarian cancer cells. Oncotarget 2017;8:93502–15.
He Y, Huang C, Cai K, Liu P, Chen X, Xu Y, et al. PRPF19 promotes tongue cancer growth and chemoradiotherapy resistance. Acta Biochim Biophys Sin. 2021;53:893–902.
Manolova V, Nyffenegger N, Flace A, Altermatt P, Varol A, Doucerain C, et al. Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemia. J Clin Investig. 2019;130:491–506.
Fogarty FM, O’Keeffe J, Zhadanov A, Papkovsky D, Ayllon V, O’Connor R. HRG-1 enhances cancer cell invasive potential and couples glucose metabolism to cytosolic/extracellular pH gradient regulation by the vacuolar-H+ ATPase. Oncogene. 2014;33:4653–63.
Palmieri F. The mitochondrial transporter family SLC25: Identification, properties and physiopathology. Mol Asp Med. 2013;34:465–84.
Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, drosophila, and humans. Science 2012;337:96–100.
Herzig S, Raemy E, Montessuit S, Veuthey JL, Zamboni N, Westermann B, et al. Identification and functional expression of the mitochondrial pyruvate carrier. Science 2012;337:93–6.
Schell JC, Olson KA, Jiang L, Hawkins AJ, Van Vranken JG, Xie J, et al. A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol Cell. 2014;56:400–13.
Zou H, Chen Q, Zhang A, Wang S, Wu H, Yuan Y, et al. MPC1 deficiency accelerates lung adenocarcinoma progression through the STAT3 pathway. Cell Death Dis. 2019;10:148.
You JH, Lee J, Roh JL. Mitochondrial pyruvate carrier 1 regulates ferroptosis in drug-tolerant persister head and neck cancer cells via epithelial-mesenchymal transition. Cancer Lett. 2021;507:40–54.
Elia I, Rossi M, Stegen S, Broekaert D, Doglioni G, van Gorsel M, et al. Breast cancer cells rely on environmental pyruvate to shape the metastatic niche. Nature. 2019;568:117–21.
Yoo HC, Park SJ, Nam M, Kang J, Kim K, Yeo JH, et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab. 2020;31:267–283. e12
Kory N, Wyant GA, Prakash G, uit de Bos J, Bottanelli F, Pacold ME, et al. SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. Science. 2018;362:eaat9528.
Acoba MG, Alpergin ESS, Renuse S, Fernández-del-Río L, Lu YW, Khalimonchuk O, et al. The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism. Cell Rep. 2021;34:108869.
Wang Y, Yen FS, Zhu XG, Timson RC, Weber R, Xing C, et al. SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells. Nature. 2021;599:136–40.
Shi X, Reinstadler B, Shah H, To TL, Byrne K, Summer L, et al. Combinatorial GxGxE CRISPR screen identifies SLC25A39 in mitochondrial glutathione transport linking iron homeostasis to OXPHOS. Nat Commun. 2022;13:2483.
Yang Y, He J, Zhang B, Zhang Z, Jia G, Liu S, et al. SLC25A1 promotes tumor growth and survival by reprogramming energy metabolism in colorectal cancer. Cell Death Dis. 2021;12:1108.
Fernandez HR. The mitochondrial citrate carrier, SLC25A1, drives stemness and therapy resistance in non-small cell lung cancer. Cell Death Differ. 2018;25:1239–58.
Tan M, Mosaoa R, Graham GT, Kasprzyk-Pawelec A, Gadre S, Parasido E, et al. Inhibition of the mitochondrial citrate carrier, Slc25a1, reverts steatosis, glucose intolerance, and inflammation in preclinical models of NAFLD/NASH. Cell Death Differ. 2020;27:2143–57.
Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2021;18:223–38.
Joly JH, Delfarah A, Phung PS, Parrish S, Graham NA. A synthetic lethal drug combination mimics glucose deprivation–induced cancer cell death in the presence of glucose. J Biol Chem. 2020;295:1350–65.
Bacci M, Lorito N, Ippolito L, Ramazzotti M, Luti S, Romagnoli S, et al. Reprogramming of amino acid transporters to support aspartate and glutamate dependency sustains endocrine resistance in breast cancer. Cell Rep. 2019;28:104–118. e8
Girardi E, César-Razquin A, Lindinger S, Papakostas K, Konecka J, Hemmerich J, et al. A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs. Nat Chem Biol. 2020;16:469–78.
Bensimon A, Pizzagalli MD, Kartnig F, Dvorak V, Essletzbichler P, Winter GE, et al. Targeted degradation of SLC transporters reveals amenability of multi-pass transmembrane proteins to ligand-induced proteolysis. Cell Chem Biol. 2020;27:728–739. e9.
Ma H, Wu Z, Peng J, Li Y, Huang H, Liao Y, et al. Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab: SLC1A5 inhibition enhances the efficacy of cetuximab. Int J Cancer. 2018;142:2578–88.
Pathria G, Scott DA, Feng Y, Sang Lee J, Fujita Y, Zhang G, et al. Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival. EMBO J. 2018;37:e99735.
Beloueche-Babari M, Wantuch S, Casals Galobart T, Koniordou M, Parkes HG, Arunan V, et al. MCT1 inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and noninvasive magnetic resonance spectroscopy. Cancer Res. 2017;77:5913–24.
Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell–derived lactic acid on human T cells. Blood. 2007;109:3812–9.
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;24:657–71.
Steggerda SM, Bennett MK, Chen J, Emberley E, Huang T, Janes JR, et al. Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J Immunother Cancer. 2017;5:101.
Ji L, Zhao X, Zhang B, Kang L, Song W, Zhao B, et al. Slc6a8-mediated creatine uptake and accumulation reprogram macrophage polarization via regulating cytokine responses. Immunity. 2019;51:272–284. e7.
Ansari RE, Craze ML, Althobiti M, Alfarsi L, Ellis IO, Rakha EA, et al. Enhanced glutamine uptake influences composition of immune cell infiltrates in breast cancer. Br J Cancer. 2020;122:94–101.
Renner K, Bruss C, Schnell A, Koehl G, Becker HM, Fante M, et al. Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy. Cell Rep. 2019;29:135–150. e9.
Huang T, Feng Q, Wang Z, Li W, Sun Z, Wilhelm J, et al. Tumor-targeted inhibition of monocarboxylate transporter 1 improves T-cell immunotherapy of solid tumors. Adv Healthcare Mater. 2020;10:2000549.
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;585:277–82.
Kaji K, Nishimura N, Seki K, Sato S, Saikawa S, Nakanishi K, et al. Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake. Int J Cancer. 2018;142:1712–22.
Armenta DA, Laqtom NN, Alchemy G, Dong W, Morrow D, Poltorack CD, et al. Ferroptosis inhibition by lysosome-dependent catabolism of extracellular protein. Cell Chem Biol. 2022;29:1588–1600. e7.
Byun JK, Lee S, Kang GW, Lee YR, Park SY, Song IS, et al. Macropinocytosis is an alternative pathway of cysteine acquisition and mitigates sorafenib-induced ferroptosis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2022;41:98.
Kurata T, Oguri T, Isobe T, Ishioka S, Yamakido M. Differential expression of facilitative glucose transporter (GLUT) genes in primary lung cancers and their liver metastases. Jpn J Cancer Res. 1999;90:1238–43.
Suganuma N, Segade F, Matsuzu K, Bowden DW. Differential expression of facilitative glucose transporters in normal and tumour kidney tissues. BJU Int. 2007;99:1143–9.
Alves VA. Characterization of monocarboxylate transporter activity in hepatocellular carcinoma. WJG. 2014;20:11780.
Wellberg EA, Johnson S, Finlay-Schultz J, Lewis AS, Terrell KL, Sartorius CA, et al. The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis. Breast Cancer Res. 2016;18:131.
Young CD, Lewis AS, Rudolph MC, Ruehle MD, Jackman MR, Yun UJ, et al. Modulation of glucose transporter 1 (GLUT1) expression levels alters mouse mammary tumor cell growth in vitro and in vivo. PLoS One. 2011;6:e23205.
Liu Y, Cao Y, Zhang W, Bergmeier S, Qian Y, Akbar H, et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther. 2012;11:1672–82.
Rosser CJ, Liu L, Sun Y, Villicana P, McCullers M, Porvasnik S, et al. Bladder cancer-associated gene expression signatures identified by profiling of exfoliated urothelia. Cancer Epidemiol Biomark Prev. 2009;18:444–53.
Flavahan WA, Wu Q, Hitomi M, Rahim N, Kim Y, Sloan AE, et al. Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat Neurosci. 2013;16:1373–82.
Guo GF, Cai YC, Zhang B, Xu RH, Qiu HJ, Xia LP, et al. Overexpression of SGLT1 and EGFR in colorectal cancer showing a correlation with the prognosis. Med Oncol. 2011;28:197–203.
Liu H, Ertay A, Peng P, Li J, Liu D, Xiong H, et al. SGLT1 is required for the survival of triple‐negative breast cancer cells via potentiation of EGFR activity. Mol Oncol. 2019;13:1874–86.
Ishikawa N, Oguri T, Isobe T, Fujitaka K, Kohno N. SGLT gene expression in primary lung cancers and their metastatic lesions. Jpn J Cancer Res. 2001;92:874–9.
Kuang H, Liao L, Chen H, Kang Q, Shu X, Wang Y. Therapeutic effect of sodium glucose co-transporter 2 inhibitor dapagliflozin on renal cell carcinoma. Med Sci Monit. 2017;23:3737–45.
Medina V. Fructose transporter Glut5 expression in clear renal cell carcinoma. Oncol Rep. 2011;25:315–23.
Zamora-Leon SP, Golde DW, Concha II, Rivas CI, Delgado-Lopez F, Baselga J, et al. Expression of the fructose transporter GLUT5 in human breast cancer. Proc Natl Acad Sci. 1996;93:1847–52.
Jin C, Gong X, Shang Y. GLUT5 increases fructose utilization in ovarian cancer. OTT. 2019;ume 12:5425–36.
Su C, Li H, Gao W. GLUT5 increases fructose utilization and promotes tumor progression in glioma. Biochem Biophys Res Commun. 2018;500:462–9.
Pinheiro C, Longatto-Filho A, Scapulatempo C, Ferreira L, Martins S, Pellerin L, et al. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch. 2008;452:139–46.
Li KKW, Pang JCS, Ching AKK, Wong CK, Kong X, Wang Y, et al. miR-124 is frequently down-regulated in medulloblastoma and is a negative regulator of SLC16A1. Hum Pathol. 2009;40:1234–43.
Hong CS, Graham NA, Gu W, Espindola Camacho C, Mah V, Maresh EL, et al. MCT1 modulates cancer cell pyruvate export and growth of tumors that co-express MCT1 and MCT4. Cell Rep. 2016;14:1590–601.
Miranda-Gonçalves V, Honavar M, Pinheiro C, Martinho O, Pires MM, Pinheiro C, et al. Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. Neuro Oncol. 2013;15:172–88.
Mathupala SP, Parajuli P, Sloan AE. Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery. 2004;55:1410–9.
Pinheiro C, Reis RM, Ricardo S, Longatto-Filho A, Schmitt F, Baltazar F. Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. J Biomed Biotechnol. 2010;2010:1–7.
Pinheiro C, Albergaria A, Paredes J, Sousa B, Dufloth R, Vieira D, et al. Monocarboxylate transporter 1 is up-regulated in basal-like breast carcinoma: MCT1 in breast cancer. Histopathology. 2010;56:860–7.
Pinheiro C, Longatto-Filho A, Ferreira L, Pereira SMM, Etlinger D, Moreira MAR, et al. Increasing expression of monocarboxylate transporters 1 and 4 along progression to invasive cervical carcinoma. Int J Gynecol Pathol. 2008;27:568–74.
Ritzhaupt A, Wood IS, Ellis A, Hosie KB, Shirazi-Beechey SP. Identification and characterization of a monocarboxylate transporter (MCT1) in pig and human colon: its potential to transport l -lactate as well as butyrate. J Physiol. 1998;513:719–32.
Lambert DW, Wood IS, Ellis A, Shirazi-Beechey SP. Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy. Br J Cancer. 2002;86:1262–9.
Pértega-Gomes N, Vizcaíno JR, Miranda-Gonçalves V, Pinheiro C, Silva J, Pereira H, et al. Monocarboxylate transporter 4 (MCT4) and CD147 overexpression is associated with poor prognosis in prostate cancer. BMC Cancer. 2011;11:312.
Zhu J, Wu YN, Zhang W, Zhang XM, Ding X, Li HQ, et al. Monocarboxylate transporter 4 facilitates cell proliferation and migration and is associated with poor prognosis in oral squamous cell carcinoma patients. PLoS One. 2014;9:e87904.
Pinheiro C, Longatto-Filho A, Simões K, Jacob CE, Bresciani CJC, Zilberstein B, et al. The prognostic value of CD147/EMMPRIN is associated with monocarboxylate transporter 1 co-expression in gastric cancer. Eur J Cancer. 2009;45:2418–24.
Guo W, Li K, Sun B, Xu D, Tong L, Yin H, et al. Dysregulated glutamate transporter SLC1A1 propels cystine uptake via Xc- for glutathione synthesis in lung cancer. Cancer Res. 2021;81:552–66.
Shimizu K, Kaira K, Tomizawa Y, Sunaga N, Kawashima O, Oriuchi N, et al. ASC amino-acid transporter 2 (ASCT2) as a novel prognostic marker in non-small cell lung cancer. Br J Cancer. 2014;110:2030–9.
Morotti M, Zois CE, El-Ansari R, Craze ML, Rakha EA, Fan SJ, et al. Increased expression of glutamine transporter SNAT2/SLC38A2 promotes glutamine dependence and oxidative stress resistance, and is associated with worse prognosis in triple-negative breast cancer. Br J Cancer. 2021;124:494–505.
Parker SJ, Amendola CR, Hollinshead KER, Yu Q, Yamamoto K, Encarnación-Rosado J, et al. Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer. Cancer Discov. 2020;10:1018–37.
Kim DK, Ahn SG, Park JC, Kanai Y, Endou H, Yoon JH. Expression of L-type Amino Acid Transporter 1 (LAT1) and 4F2 Heavy Chain (4F2hc) in oral squamous cell carcinoma and its precusor lesions. Anticancer Res. 2004;24:1671–5.
Kobayashi K, Ohnishi A, Promsuk J, Shimizu S, Kanai Y, Shiokawa Y, et al. Enhanced tumor growth elicited by L-type amino acid transporter 1 in human malignant glioma cells. Neurosurgery. 2008;62:493–504.
Ji X, Qian J, Rahman SMJ, Siska PJ, Zou Y, Harris BK, et al. xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression. Oncogene 2018;37:5007–19.
Yang Y, Yee D. IGF-I regulates redox status in breast cancer cells by activating the amino acid transport molecule xC −. Cancer Res. 2014;74:2295–305.
Guo W, Zhao Y, Zhang Z, Tan N, Zhao F, Ge C, et al. Disruption of xCT inhibits cell growth via the ROS/autophagy pathway in hepatocellular carcinoma. Cancer Lett. 2011;312:55–61.
Timmerman LA, Holton T, Yuneva M, Louie RJ, Padró M, Daemen A, et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell. 2013;24:450–65.
Shao H, Mohamed EM, Xu GG, Waters M, Jing K, Ma Y, et al. Carnitine palmitoyltransferase 1A functions to repress FoxO transcription factors to allow cell cycle progression in ovarian cancer. Oncotarget. 2016;7:3832–46.
Xu L, Li X, Cai M, Chen J, Li X, Wu WKK, et al. Increased expression of Solute carrier family 12 member 5 via gene amplification contributes to tumour progression and metastasis and associates with poor survival in colorectal cancer. Gut. 2016;65:635–46.
Yang GP, He WP, Tan JF, Yang ZX, Fan RR, Ma NF, et al. Overexpression of SLC12A5 is associated with tumor progression and poor survival in ovarian carcinoma. Int J Gynecol Cancer. 2019;29:1280–4.
Mohelnikova-Duchonova B, Brynychova V, Hlavac V, Kocik M, Oliverius M, Hlavsa J, et al. The association between the expression of solute carrier transporters and the prognosis of pancreatic cancer. Cancer Chemother Pharm. 2013;72:669–82.
Jung Y, Jun Y, Lee HY, Kim S, Jung Y, Keum J, et al. Characterization of SLC22A18 as a tumor suppressor and novel biomarker in colorectal cancer. Oncotarget. 2015;6:25368–80.
Cheng X, Wei L, Huang X, Zheng J, Shao M, Feng T, et al. Solute carrier family 39 member 6 gene promotes aggressiveness of esophageal carcinoma cells by increasing intracellular levels of zinc, activating phosphatidylinositol 3-kinase signaling, and up-regulating genes that regulate metastasis. Gastroenterology. 2017;152:25.
Wong CC, Qian Y, Li X, Xu J, Kang W, Tong JH, et al. SLC25A22 promotes proliferation and survival of colorectal cancer cells with KRAS mutations and xenograft tumor progression in mice via intracellular synthesis of aspartate. Gastroenterology. 2016;151:945–960. e6.
Zou H. MPC1 deficiency accelerates lung adenocarcinoma progression through the STAT3 pathway. Cell Death Dis. 2019;10:148.
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;513:559–63.
ZCN was supported by the Michigan Postdoctoral Pioneer Program at the University of Michigan Medical School, NIH/NCI grant K99CA267176 and NIH/NIGMS grant R25GM143298. MP was supported by NIH/NCI grants R01CA151588 and R01CA198074. CAL was supported by the NIH/NCI grants R37CA237421, R01CA248160, and R01CA244931, and MP and CAL by UMCCC Core Grant (P30CA046592). SEK was supported by the National Research Foundation of Korea (NRF) grant (2020R1C1C1013220). The funders had no role in the content and publication of this manuscript. The authors apologize to researchers whose relevant work could not be cited in this review due to space limitations.
CAL has received consulting fees from Astellas Pharmaceuticals, Odyssey Therapeutics, and T-Knife Therapeutics, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015). Other authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Nwosu, Z.C., Song, M.G., di Magliano, M.P. et al. Nutrient transporters: connecting cancer metabolism to therapeutic opportunities. Oncogene 42, 711–724 (2023). https://doi.org/10.1038/s41388-023-02593-x