The microenvironment in cancerous tissues is immunosuppressive and pro-tumorigenic, whereas the microenvironment of tissues affected by chronic inflammatory disease is pro-inflammatory and anti-resolution. Despite these opposing immunological states, the metabolic states in the tissue microenvironments of cancer and inflammatory diseases are similar: both are hypoxic, show elevated levels of lactate and other metabolic by-products and have low levels of nutrients. In this Review, we describe how the bioavailability of lactate differs in the microenvironments of tumours and inflammatory diseases compared with normal tissues, thus contributing to the establishment of specific immunological states in disease. A clear understanding of the metabolic signature of tumours and inflammatory diseases will enable therapeutic intervention aimed at resetting the bioavailability of metabolites and correcting the dysregulated immunological state, triggering beneficial cytotoxic, inflammatory responses in tumours and immunosuppressive responses in chronic inflammation.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016).
Macintyre, A. N. et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61–72 (2014).
Gerriets, V. A. et al. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J. Clin. Invest. 125, 194–207 (2015).
Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293 e7 (2017).
Pucino, V. et al. Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4+ T cell metabolic rewiring. Cell Metab. 30, 1055–1074.e8 (2019). This study shows how SLC5A12-driven lactate uptake leads to a stepwise reprogramming of cellular metabolism, which supports a pro-inflammatory response by CD4 + T cells.
Song, Y. J. et al. Inhibition of lactate dehydrogenase A suppresses inflammatory response in RAW 264.7 macrophages. Mol. Med. Rep. 19, 629–637 (2019).
Le, A. et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl Acad. Sci. USA 107, 2037–2042 (2010).
Certo, M., Marone, G., de Paulis, A., Mauro, C. & Pucino, V. Lactate: fueling the fire starter. Wiley Interdiscip. Rev. Syst. Biol. Med. 16, e1474 (2019).
Husain, Z., Huang, Y., Seth, P. & Sukhatme, V. P. Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J. Immunol. 191, 1486–1495 (2013).
Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).
Chang, C. H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).
Israelsen, W. J. & Vander Heiden, M. G. Pyruvate kinase: function, regulation and role in cancer. Semin. Cell Dev. Biol. 43, 43–51 (2015).
Lunt, S. Y. et al. Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Mol. Cell 57, 95–107 (2015).
Zhang, Z. et al. PKM2, function and expression and regulation. Cell Biosci. 9, 52 (2019).
Day, A. S., Judd, T., Lemberg, D. A. & Leach, S. T. Fecal M2-PK in children with Crohn’s disease: a preliminary report. Dig. Dis. Sci. 57, 2166–2170 (2012).
Tang, Q. et al. Pyruvate kinase M2 regulates apoptosis of intestinal epithelial cells in Crohn’s disease. Dig. Dis. Sci. 60, 393–404 (2015).
Shirai, T. et al. The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J. Exp. Med. 213, 337–354 (2016).
Andersson, U. et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192, 565–570 (2000).
Weyand, C. M., Zeisbrich, M. & Goronzy, J. J. Metabolic signatures of T-cells and macrophages in rheumatoid arthritis. Curr. Opin. Immunol. 46, 112–120 (2017).
Angiari, S. et al. Pharmacological activation of pyruvate kinase M2 inhibits CD4+ T cell pathogenicity and suppresses autoimmunity. Cell Metab. 31, 391–405.e8 (2019).
Palsson-McDermott, E. M. et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab. 21, 347 (2015).
Mukherjee, J. et al. PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells. Int. J. Cancer 139, 99–111 (2016).
Huang, L. et al. Interaction with pyruvate kinase M2 destabilizes tristetraprolin by proteasome degradation and regulates cell proliferation in breast cancer. Sci. Rep. 6, 22449 (2016).
Liang, J. et al. Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2. Cell Res. 27, 329–351 (2017).
Azoitei, N. et al. PKM2 promotes tumor angiogenesis by regulating HIF-1α through NF-κB activation. Mol. Cancer 15, 3 (2016).
Palsson-McDermott, E. M. et al. Pyruvate kinase M2 is required for the expression of the immune checkpoint PD-L1 in immune cells and tumors. Front. Immunol. 8, 1300 (2017).
Voena, C. & Chiarle, R. Advances in cancer immunology and cancer immunotherapy. Discov. Med. 21, 125–133 (2016).
Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).
Zhang, W. et al. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 178, 176–189.e15 (2019).
Anderson, M., Marayati, R., Moffitt, R. & Yeh, J. J. Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer. Oncotarget 8, 56081–56094 (2016).
Qian, X., Yang, Z., Mao, E. & Chen, E. Regulation of fatty acid synthesis in immune cells. Scand. J. Immunol. 88, e12713 (2018).
Batista-Gonzalez, A., Vidal, R., Criollo, A. & Carreño, L. J. New insights on the role of lipid metabolism in the metabolic reprogramming of macrophages. Front. Immunol. 10, 2993 (2020).
Wei, X. et al. Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature 539, 294–298 (2016).
Berod, L. et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20, 1327–1333 (2014).
Rohrig, F. & Schulze, A. The multifaceted roles of fatty acid synthesis in cancer. Nat. Rev. Cancer 16, 732–749 (2016).
Rysman, E. et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res. 70, 8117–8126 (2010).
Rehman, A. et al. Role of fatty-acid synthesis in dendritic cell generation and function. J. Immunol. 190, 4640–4649 (2013).
Bergersen, L. H. Is lactate food for neurons? Comparison of monocarboxylate transporter subtypes in brain and muscle. Neuroscience 145, 11–19 (2007).
Magistretti, P. J. Neuron–glia metabolic coupling and plasticity. J. Exp. Biol. 209, 2304–2311 (2006).
Pucino, V., Bombardieri, M., Pitzalis, C. & Mauro, C. Lactate at the crossroads of metabolism, inflammation, and autoimmunity. Eur. J. Immunol. 47, 14–21 (2017).
Certo, M. Endothelial and T cell crosstalk: targeting metabolism as a therapeutic approach in chronic inflammation. Br. J. Pharmacol. https://doi.org/10.1111/bph.15002 (2020).
Lee, D. C. et al. A lactate-induced response to hypoxia. Cell 161, 595–609 (2015). This study explains the role of lactate in hypoxia-induced diseases and provides a new molecular basis for the development of therapeutic strategies.
Haas, R. et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 13, e1002202 (2015).
Yang, Z., Fujii, H., Mohan, S. V., Goronzy, J. J. & Weyand, C. M. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J. Exp. Med. 210, 2119–2134 (2013).
Yang, Z. et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl. Med. 8, 331ra38 (2016).
Shen, Y. et al. Metabolic control of the scaffold protein TKS5 in tissue-invasive, pro-inflammatory T cells. Nat. Immunol. 18, 1025–1034 (2017).
Shime, H. et al. Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway. J. Immunol. 180, 7175–7183 (2008).
Yabu, M. et al. IL-23-dependent and -independent enhancement pathways of IL-17A production by lactic acid. Int. Immunol. 23, 29–41 (2011).
Humby, F. et al. Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients. Ann. Rheum. Dis. 78, 761–772 (2019).
Garcia-Carbonell, R. et al. Critical role of glucose metabolism in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Rheumatol. 68, 1614–1626 (2016).
Gobelet, C. & Gerster, J. C. Synovial fluid lactate levels in septic and non-septic arthritides. Ann. Rheum. Dis. 43, 742–745 (1984).
Pejovic, M., Stankovic, A. & Mitrovic, D. R. Lactate dehydrogenase activity and its isoenzymes in serum and synovial fluid of patients with rheumatoid arthritis and osteoarthritis. J. Rheumatol. 19, 529–533 (1992).
Lindy, S., Uitto, J., Turto, H., Rokkanen, P. & Vainio, K. Lactate dehydrogenase in the synovial tissue in rheumatoid arthritis: total activity and isoenzyme composition. Clin. Chim. Acta 31, 19–23 (1971).
Hoque, R., Farooq, A., Ghani, A., Gorelick, F. & Mehal, W. Z. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology 146, 1763–1774 (2014).
Roland, C. L. Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Res. 74, 5301–5310 (2014).
Racker, E. Bioenergetics and the problem of tumor growth. Am. Sci. 60, 56–63 (1972).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial–mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
Pastorek, J. & Pastorekova, S. Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: from biology to clinical use. Semin. Cancer Biol. 31, 52–64 (2015).
Shen, Y. et al. The switch from ER stress-induced apoptosis to autophagy via ROS-mediated JNK/p62 signals: a survival mechanism in methotrexate-resistant choriocarcinoma cells. Exp. Cell Res. 334, 207–218 (2015).
Calcinotto, A. et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 72, 2746–2756 (2012).
Ippolito, L., Morandi, A., Giannoni, E. & Chiarugi, P. Lactate: a metabolic driver in the tumour landscape. Trends Biochem. Sci. 44, 153–166 (2019).
Balgi, A. D. et al. Regulation of mTORC1 signaling by pH. PLoS ONE 6, e2154 (2011).
El-Kenawi, A. E. et al. Abstract 3213: extracellular acidosis alters polarization of macrophages. Cancer Res. 75, 15 (2015).
Xie, D., Zhu, S. & Bai, L. Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling. Sci. China Life Sci. 59, 1290–1296 (2016).
Langin, D. Adipose tissue lipolysis revisited (again!): lactate involvement in insulin antilipolytic action. Cell Metab. 11, 242–243 (2010).
Goetze, K., Walenta, S., Ksiazkiewicz, M., Kunz-Schughart, L. A. & Mueller-Klieser, W. Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release. Int. J. Oncol. 39, 453–463 (2011).
Husain, Z., Seth, P. & Sukhatme, V. P. Tumor-derived lactate and myeloid-derived suppressor cells: linking metabolism to cancer immunology. Oncoimmunology 2, e26383 (2013).
Ranganathan, P. et al. GPR81, a cell-surface receptor for lactate, regulates intestinal homeostasis and protects mice from experimental colitis. J. Immunol. 200, 1781–1789 (2018).
Chen, P. et al. Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis. Proc. Natl Acad. Sci. USA 114, 580–585 (2017).
Pioli, P. A., Hamilton, B. J., Connolly, J. E., Brewer, G. & Rigby, W. F. Lactate dehydrogenase is an AU-rich element-binding protein that directly interacts with AUF1. J. Biol. Chem. 277, 35738–35745 (2002).
Ye, H. et al. Tumor-associated macrophages promote progression and the Warburg effect via CCL18/NF-kB/VCAM-1 pathway in pancreatic ductal adenocarcinoma. Cell Death Dis. 9, 453 (2018).
Dietl, K. et al. Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes. J. Immunol. 184, 1200–1209 (2010). Together with Haas et al. (2015) and Calcinotto et al. (2012), this study demonstrates that high lactic acid production and proton accumulation inhibit the function of immune cells and represent a mechanism of immune escape.
Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014). This study demonstrates a key role for lactate in the polarization of macrophages towards an M2-like phenotype and subsequent promotion of tumour growth.
Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019). This study highlights how lactate, in addition to its metabolic functions, can induce epigenetic modifications resulting in increased transcription of homeostatic genes.
Gottfried, E. et al. Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107, 2013–2021 (2006).
Puig-Kroger, A. et al. Peritoneal dialysis solutions inhibit the differentiation and maturation of human monocyte-derived dendritic cells: effect of lactate and glucose-degradation products. J. Leukoc. Biol. 73, 482–492 (2003).
Fischer, K. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819 (2007).
Xia, H. et al. Suppression of FIP200 and autophagy by tumor-derived lactate promotes naive T cell apoptosis and affects tumor immunity. Sci. Immunol. 2, eaan4631 (2017).
Brooks, G. A. The science and translation of lactate shuttle theory. Cell Metab. 27, 757–785 (2018).
Leiblich, A. et al. Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer. Oncogene 25, 2953–2960 (2006).
Maekawa, M. et al. Promoter hypermethylation in cancer silences LDHB, eliminating lactate dehydrogenase isoenzymes 1–4. Clin. Chem. 49, 1518–1520 (2003).
Cui, J. et al. Suppressed expression of LDHB promotes pancreatic cancer progression via inducing glycolytic phenotype. Med. Oncol. 32, 143 (2015).
Shi, L. et al. SIRT5-mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer. Mol. Oncol. 13, 358–375 (2019).
Kurpinska, A. et al. Proteomic characterization of early lung response to breast cancer metastasis in mice. Exp. Mol. Pathol. 107, 129–140 (2019).
Lemma, S. et al. MDA-MB-231 breast cancer cells fuel osteoclast metabolism and activity: a new rationale for the pathogenesis of osteolytic bone metastases. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 3254–3264 (2017).
Kumar, V. B., Viji, R. I., Kiran, M. S. & Sudhakaran, P. R. Endothelial cell response to lactate: implication of PAR modification of VEGF. J. Cell Physiol. 211, 477–485 (2007).
Trabold, O. et al. Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Wound Repair Regen. 11, 504–509 (2003).
Beckert, S. et al. Lactate stimulates endothelial cell migration. Wound Repair Regen. 14, 321–324 (2006).
Vegran, F., Boidot, R., Michiels, C., Sonveaux, P. & Feron, O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 71, 2550–2560 (2011). This study shows how lactate released by tumour cells can enter endothelial cells and stimulate angiogenesis and tumour growth.
Walenta, S. & Mueller-Klieser, W. F. Lactate: mirror and motor of tumor malignancy. Semin. Radiat. Oncol. 14, 267–274 (2004).
Baumann, F. et al. Lactate promotes glioma migration by TGF-β2-dependent regulation of matrix metalloproteinase-2. Neuro Oncol. 11, 368–380 (2009).
Lu, W. & Kang, Y. Epithelial–mesenchymal plasticity in cancer progression and metastasis. Dev. Cell 49, 361–374 (2019).
Celia-Terrassa, T. & Kang, Y. Metastatic niche functions and therapeutic opportunities. Nat. Cell Biol. 20, 868–877 (2018).
Polanski, R. et al. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin. Cancer Res. 20, 926–937 (2014).
Mathupala, S. P., Parajuli, P. & Sloan, A. E. Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery 55, 1410–1419 (2004). Together with Polanski et al. (2014), this study suggests that targeting lactate transporters can be a useful strategy for the inhibition of tumour growth.
Hong, C. S. et al. MCT1 modulates cancer cell pyruvate export and growth of tumors that co-express MCT1 and MCT4. Cell Rep. 14, 1590–1601 (2016).
Zdralevic, M. et al. Disrupting the ‘Warburg effect’ re-routes cancer cells to OXPHOS offering a vulnerability point via ‘ferroptosis’-induced cell death. Adv. Biol. Regul. 68, 55–63 (2018).
Xie, H. et al. Targeting lactate dehydrogenase-A inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metab. 19, 795–809 (2014).
Granchi, C. et al. Discovery of N-hydroxyindole-based inhibitors of human lactate dehydrogenase isoform A (LDH-A) as starvation agents against cancer cells. J. Med. Chem. 54, 1599–1612 (2011).
Manerba, M. et al. Galloflavin (CAS 568–80-9): a novel inhibitor of lactate dehydrogenase. ChemMedChem 7, 311–317 (2012).
Maftouh, M. et al. Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia. Br. J. Cancer 110, 172–182 (2014).
Allison, S. J. et al. Identification of LDH-A as a therapeutic target for cancer cell killing via (i) p53/NAD(H)-dependent and (ii) p53-independent pathways. Oncogenesis 3, e102 (2014).
Braaten, T. J. et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann. Rheum. Dis. 79, 332–338 (2020).
Moreno-Aurioles, V. R. & Sobrino, F. Glucocorticoids inhibit fructose 2,6-bisphosphate synthesis in rat thymocytes. Opposite effect of cycloheximide. Biochim. Biophys. Acta 1091, 96–100 (1991).
Kuhnke, A. et al. Bioenergetics of immune cells to assess rheumatic disease activity and efficacy of glucocorticoid treatment. Ann. Rheum. Dis. 62, 133–139 (2003).
Biniecka, M. et al. Redox-mediated angiogenesis in the hypoxic joint of inflammatory arthritis. Arthritis Rheumatol. 66, 3300–3310 (2014).
McGarry, T. et al. JAK/STAT blockade alters synovial bioenergetics, mitochondrial function, and proinflammatory mediators in rheumatoid arthritis. Arthritis Rheumatol. 70, 1959–1970 (2018).
Okano, T. et al. 3-Bromopyruvate ameliorate autoimmune arthritis by modulating TH17/Treg cell differentiation and suppressing dendritic cell activation. Sci. Rep. 7, 42412 (2017).
Bustamante, M. F. et al. Hexokinase 2 as a novel selective metabolic target for rheumatoid arthritis. Ann. Rheum. Dis. 77, 1636–1643 (2018).
Yin, Y. et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci. Transl. Med. 7, 274ra18 (2015).
Yin, Y. et al. Glucose oxidation is critical for CD4+ T cell activation in a mouse model of systemic lupus erythematosus. J. Immunol. 196, 80–90 (2016).
Abboud, G. et al. Inhibition of glycolysis reduces disease severity in an autoimmune model of rheumatoid arthritis. Front. Immunol. 9, 1973 (2018).
Guak, H. et al. Glycolytic metabolism is essential for CCR7 oligomerization and dendritic cell migration. Nat. Commun. 9, 2463 (2018).
Schilling, S., Goelz, S., Linker, R., Luehder, F. & Gold, R. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin. Exp. Immunol. 145, 101–107 (2006).
Smith, M. D. et al. Dimethyl fumarate alters B-cell memory and cytokine production in MS patients. Ann. Clin. Transl. Neurol. 4, 351–355 (2017).
Smith, M. D., Calabresi, P. A. & Bhargava, P. Dimethyl fumarate treatment alters NK cell function in multiple sclerosis. Eur. J. Immunol. 48, 380–383 (2018).
Luckel, C. et al. IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis. Nat. Commun. 10, 5722 (2019).
Deshmukh, P. et al. The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases. Biophys. Rev. 9, 41–56 (2017).
Tokubuchi, I. et al. Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats. PLoS ONE 12, e0171293 (2017).
Kang, K. Y. et al. Metformin downregulates TH17 cells differentiation and attenuates murine autoimmune arthritis. Int. Immunopharmacol. 16, 85–92 (2013).
Zarrouk, M. et al. Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells. PLoS ONE 9, e106710 (2014).
Fujii, W. et al. Monocarboxylate transporter 4, associated with the acidification of synovial fluid, is a novel therapeutic target for inflammatory arthritis. Arthritis Rheumatol. 67, 2888–2896 (2015). This study suggests that the lactate transporter MCT4 is a potential therapeutic target for inflammatory arthritis.
Littlewood-Evans, A. et al. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J. Exp. Med. 213, 1655–1662 (2016).
Qiu, J. et al. Acetate promotes T cell effector function during glucose restriction. Cell Rep. 27, 2063–2074 (2019).
Marone, G. et al. Prostaglandin D2 receptor antagonists in allergic disorders: safety, efficacy, and future perspectives. Expert. Opin. Investig. Drugs 28, 73–84 (2019).
Li, W. et al. Targeting T cell activation and lupus autoimmune phenotypes by inhibiting glucose transporters. Front. Immunol. 10, 833 (2019).
Zhang, Z. et al. Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis. Nat. Med. 24, 617–627 (2018).
Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166 (2016).
Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).
C.M. was supported by a Medical Research Council Project Grant (MR/T016736/1), a British Heart Foundation Fellowship (FS/12/38/29640), a Fondazione Cariplo Project Grant (2015-0552) and a University of Birmingham Professorial Research Fellowship. P.-C.H. was supported, in part, by a Swiss National Science Foundation project grant (31003A_182470), a European Research Council Starting Grant (802773-MitoGuide), an EMBO Young Investigator award and a Cancer Research Institute Clinic and Laboratory Integration Program (CLIP) Investigator award. Original figures were created with BioRender.com.
P.-C.H. is scientific adviser for Elixiron Immunotherapeutics and receives research funding from Roche. P.-C.H. has received honorarium from Chungai and Pfizer. The other authors declare no competing interests.
Peer review information
Nature Reviews Immunology thanks L. O’Neill and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Pentose phosphate pathway
A metabolic pathway that is parallel to glycolysis and that generates NADPH, a substrate used for lipogenesis and glutathione regeneration, and ribose 5-phosphate, a precursor for nucleotide synthesis in proliferating cells.
- Warburg effect
A phenomenon observed in rapidly dividing cells or when robust transient responses are needed that is characterized by the conversion of glucose into lactate, even in the presence of normal levels of oxygen.
- Experimental autoimmune encephalomyelitis
(EAE). A demyelinating disease of the central nervous system used as a common animal model for multiple sclerosis.
- Tumour-associated macrophages
Immune cells that induce an immunosuppressive tumour microenvironment through the release of growth factors, proteolytic enzymes and inhibitory immune checkpoint proteins.
- Myeloid-derived suppressor cells
A group of phenotypically heterogeneous myeloid cells that contribute to tumour expansion and chronic inflammation progression by inducing immunosuppressive mechanisms, angiogenesis and drug resistance.
- Mitochondrial antiviral signalling protein
(MAVS). A mitochondrial adaptor protein activation of which induces the release of cytokines and triggers an immune response.
About this article
Cite this article
Certo, M., Tsai, CH., Pucino, V. et al. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-0406-2