Metabolic Modulation of Immunity: A New Concept in Cancer Immunotherapy

Immunotherapy shifted the paradigm of cancer treatment. The clinical approval of immune checkpoint blockade and adoptive cell transfer led to considerable success in several tumor types. However, for a significant number of patients, these therapies have proven ineffective. Growing evidence shows that the metabolic requirements of immune cells in the tumor microenvironment (TME) greatly influence the success of immunotherapy. It is well established that the TME influences energy consumption and metabolic reprogramming of immune cells, often inducing them to become tolerogenic and inefficient in cancer cell eradication. Increasing nutrient availability using pharmacological modulators of metabolism or antibodies targeting specific immune receptors are strategies that support energetic rewiring of immune cells and boost their anti-tumor capacity. In this review, we describe the metabolic features of the diverse immune cell types in the context of the TME and discuss how these immunomodulatory strategies could synergize with immunotherapy to circumvent its current limitations. Immunotherapy shifted the paradigm of cancer treatment. The clinical approval of immune checkpoint blockade and adoptive cell transfer led to considerable success in several tumor types. However, for a significant number of patients, these therapies have proven ineffective. Growing evidence shows that the metabolic requirements of immune cells in the tumor microenvironment (TME) greatly influence the success of immunotherapy. It is well established that the TME influences energy consumption and metabolic reprogramming of immune cells, often inducing them to become tolerogenic and inefficient in cancer cell eradication. Increasing nutrient availability using pharmacological modulators of metabolism or antibodies targeting specific immune receptors are strategies that support energetic rewiring of immune cells and boost their anti-tumor capacity. In this review, we describe the metabolic features of the diverse immune cell types in the context of the TME and discuss how these immunomodulatory strategies could synergize with immunotherapy to circumvent its current limitations. Immune checkpoint blockade (ICB) has transformed cancer treatment. Antibodies targeting the inhibitory T cell receptors CTLA-4 and PD-1 have significantly improved patient survival in many cases (Schadendorf et al., 2015Schadendorf D. Hodi F.S. Robert C. Weber J.S. Margolin K. Hamid O. Patt D. Chen T.T. Berman D.M. Wolchok J.D. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma.J. Clin. Oncol. 2015; 33: 1889-1894Crossref PubMed Scopus (1069) Google Scholar), but numerous cancers remain refractory to this approach (Gauci et al., 2019Gauci M.-L. Lanoy E. Champiat S. Caramella C. Ammari S. Aspeslagh S. Varga A. Baldini C. Bahleda R. Gazzah A. et al.Long-term survival in patients responding to anti-PD-1/PD-L1 therapy and disease outcome upon treatment discontinuation.Clin. Cancer Res. 2019; 25: 946-956Crossref PubMed Scopus (24) Google Scholar). Some tumors lack immune cell infiltrates ("cold tumors"), rendering them unaffected by ICB (Fares et al., 2019Fares C.M. Van Allen E.M. Drake C.G. Allison J.P. Hu-Lieskovan S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients?.Am. Soc. Clin. Oncol. Educ. Book. 2019; 39: 147-164Crossref PubMed Google Scholar). Other "hot tumors" contain immune cell infiltrates that support "immunoediting," in which cancer cells expressing neoepitopes are selected and resist the antigen-specific anti-tumor effector T cell (Teff cell) response. This resistance culminates in Teff cell exhaustion, which is closely related to metabolic changes in the tumor microenvironment (TME). The TME influences energy consumption and metabolic reprogramming in immune cells, often inducing them to become tolerogenic and inefficient in cancer cell eradication. In this review, we discuss how modulating the metabolism of immune cells ("immunometabolism") can improve the efficacy and durability of anti-tumor responses, boosting the success of anti-cancer immunotherapy. The TME contains cancer cells, immune cells, fibroblasts, blood vessels, extracellular matrix, and signaling molecules. The interplay among TME cell populations and their differing energetic needs shapes tumor development (Hanahan and Weinberg, 2011Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (29323) Google Scholar). To cope with their rapid proliferation, cancer cells implement a metabolic switch characterized by increased consumption of glucose and amino acids (AAs). Indeed, although they retain functional mitochondria and the capacity to engage oxidative phosphorylation (OXPHOS), cancer cells use glucose as their main energy source (Morais et al., 1994Morais R. Zinkewich-Péotti K. Parent M. Wang H. Babai F. Zollinger M. Tumor-forming ability in athymic nude mice of human cell lines devoid of mitochondrial DNA.Cancer Res. 1994; 54: 3889-3896PubMed Google Scholar; Tan et al., 2015Tan A.S. Baty J.W. Dong L.F. Bezawork-Geleta A. Endaya B. Goodwin J. Bajzikova M. Kovarova J. Peterka M. Yan B. et al.Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA.Cell Metab. 2015; 21: 81-94Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar). Glucose and AAs are catabolized into carbon intermediates needed to assemble macromolecules, fuel ATP production in the electron transport chain (ETC), and help to maintain cellular redox capacity (Pavlova and Thompson, 2016Pavlova N.N. Thompson C.B. The emerging hallmarks of cancer metabolism.Cell Metab. 2016; 23: 27-47Abstract Full Text Full Text PDF PubMed Scopus (1296) Google Scholar). A cancer cell’s ability to increase its metabolic rate independently of external growth stimuli rests on its high mutational burden. Heterogeneity in the mutations exhibited by different cancer cells accounts for their distinct metabolic adaptations. Interestingly, excessive nutrient uptake by a tumor imposes metabolic stress on immune cells infiltrating the TME (Franchina et al., 2018bFranchina D.G. He F. Brenner D. Survival of the fittest: cancer challenges T cell metabolism.Cancer Lett. 2018; 412: 216-223Crossref PubMed Scopus (12) Google Scholar) (Figure 1). Glucose and glutamine deprivation prevent immune cells from switching from OXPHOS to glycolysis, compromising their function (see below). In addition, even in the presence of oxygen, glycolysis-derived pyruvate is not used to fuel the tricarboxylic acid (TCA) cycle in a tumor cell but is converted to lactate by lactate dehydrogenase (LDHA), a principle known as the Warburg effect (Warburg, 1956Warburg O. On the origin of cancer cells.Science. 1956; 123: 309-314Crossref PubMed Google Scholar; Shim et al., 1997Shim H. Dolde C. Lewis B.C. Wu C.-S. Dang G. Jungmann R.A. Dalla-Favera R. Dang C.V. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth.Proc. Natl. Acad. Sci. USA. 1997; 94: 6658-6663Crossref PubMed Scopus (716) Google Scholar). The excess lactate produced by the proliferating cancer cells is exported by monocarboxylate transporters (MCTs) and increases the acidity of the TME (Halestrap, 2012Halestrap A.P. The monocarboxylate transporter family--Structure and functional characterization.IUBMB Life. 2012; 64: 1-9Crossref PubMed Scopus (285) Google Scholar), further interfering with immune cell metabolism (Renner et al., 2019Renner K. Bruss C. Schnell A. Koehl G. Becker H.M. Fante M. Menevse A.N. Kauer N. Blazquez R. Hacker L. et al.Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy.Cell Rep. 2019; 29: 135-150.e9Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). In melanoma patients, increased LDHA and lactate levels correlate with reduced survival (Brand et al., 2016Brand A. Singer K. Koehl G.E. Kolitzus M. Schoenhammer G. Thiel A. Matos C. Bruss C. Klobuch S. Peter K. et al.LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells.Cell Metab. 2016; 24: 657-671Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar). Moreover, lactate promotes tumor angiogenesis because it stabilizes hypoxia-inducible factor 1-alpha (Hif1α), which supports cancer cell survival under the hypoxic conditions often found in the TME. Hif1α also activates nuclear factor kappa B (NF-κB) in stromal cells and their secretion of vascular endothelial growth factor (VEGF) (Sonveaux et al., 2012Sonveaux P. Copetti T. De Saedeleer C.J. Végran F. Verrax J. Kennedy K.M. Moon E.J. Dhup S. Danhier P. Frérart F. et al.Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis.PLoS ONE. 2012; 7: e33418Crossref PubMed Scopus (226) Google Scholar; Végran et al., 2011Végran 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. 2011; 71: 2550-2560Crossref PubMed Scopus (366) Google Scholar). Neoangiogenesis is then induced and sustains tumor growth and invasion. In addition, Hif1α promotes the expression of ligands for PD-1 and CTLA-4 on cancer cells. These ligands deliver an inhibitory signal to Teff cells that suppresses their anti-tumor functions. Besides glucose and glutamine, a solid tumor often consumes tryptophan. This AA is metabolized by indoleamine 2,3-dioxygenase (IDO) to kynurenine. Kynurenine not only promotes tumor cell survival and motility but also supports the generation of regulatory T cells (Treg cells), which suppress anti-tumor Teff cell responses. Increased IDO expression therefore correlates with tumor progression and poor prognosis (Liu et al., 2016Liu H. Shen Z. Wang Z. Wang X. Zhang H. Qin J. Qin X. Xu J. Sun Y. Increased expression of IDO associates with poor postoperative clinical outcome of patients with gastric adenocarcinoma.Sci. Rep. 2016; 6: 21319Crossref PubMed Scopus (33) Google Scholar). Rapidly dividing cancer cells tend to accumulate reactive oxygen species (ROS). High levels of ROS are generally detrimental to normal cells. For example, accumulating ROS in T cells shuts down Teff cell responses by preventing the metabolic reprogramming that occurs upon activation (Mak et al., 2017Mak T.W. Grusdat M. Duncan G.S. Dostert C. Nonnenmacher Y. Cox M. Binsfeld C. Hao Z. Brüstle A. Itsumi M. et al.Glutathione primes T cell metabolism for inflammation.Immunity. 2017; 46: 675-689Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). In contrast, malignant cells acquire potent antioxidant capacity that allows ROS to act as pro-tumorigenic signaling molecules (Reczek and Chandel, 2017Reczek C.R. Chandel N.S. The two faces of reactive oxygen species in cancer.Ann. Rev. Cancer Biol. 2017; 1: 79-98Crossref Google Scholar; Harris et al., 2015Harris I.S. Treloar A.E. Inoue S. Sasaki M. Gorrini C. Lee K.C. Yung K.Y. Brenner D. Knobbe-Thomsen C.B. Cox M.A. et al.Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression.Cancer Cell. 2015; 27: 211-222Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar) and to stabilize Hif1α (Chandel et al., 1998Chandel N.S. Maltepe E. Goldwasser E. Mathieu C.E. Simon M.C. Schumacker P.T. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription.Proc. Natl. Acad. Sci. USA. 1998; 95: 11715-11720Crossref PubMed Scopus (1368) Google Scholar). Although tumors share metabolic features that may appear to make them generally susceptible to therapeutic targeting, it has become evident that different types of cancers and even distinct regions of the same tumor show great heterogeneity and plasticity in their metabolic adaptations, allowing malignant cells to select for mechanisms that confer resistance to therapy (Kim and DeBerardinis, 2019Kim J. DeBerardinis R.J. Mechanisms and implications of metabolic heterogeneity in cancer.Cell Metab. 2019; 30: 434-446Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar). Thus, it may be wise to shift the targeting focus from the highly flexible tumor cell to a more-rigid player: the immune system. Although some immune-based strategies have proven to be powerful therapeutic alternatives to conventional cancer treatments, there remain several drawbacks. Improvements are needed to increase the efficacy of immunotherapy. Metabolic manipulation via genetic or pharmacological approaches may be a means of achieving this goal. Below, we review the main metabolic features of various immune cell types and describe how they are influenced by the TME. We also discuss current efforts to modulate these metabolic characteristics in order to improve cancer immunotherapy. These approaches may improve immune cell effector functions by themselves or through synergy with other metabolic modulators. T cells are major players in anti-tumor defense because they mount antigen-specific responses against cancer cells. Some activated T cells directly kill tumor cells by producing cytotoxic components. Others secrete signaling molecules, such as cytokines, that activate or prime other types of immune cells. The most successful cancer immunotherapy strategies to date are T-cell-based therapies, specifically ICB and adoptive cell transfer (ACT) (Figure 2). ICB aims to enhance anti-tumor T cell responses by using monoclonal antibodies (mAbs) to suppress the functions of T cell inhibitory receptors, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (ipilimumab) and programmed cell death-1 (PD-1) (nivolumab and pembrolizumab) (Hargadon et al., 2018Hargadon K.M. Johnson C.E. Williams C.J. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors.Int. Immunopharmacol. 2018; 62: 29-39Crossref PubMed Scopus (155) Google Scholar). In the later stages of a physiological immune response, CTLA-4 becomes expressed mainly on activated T cells and interacts with the co-stimulatory molecules CD80 or CD86 on antigen-presenting cells (APCs) to block the acquisition of Teff cell function. The immune response is shut down before excessive collateral damage is inflicted on bystander cells. Ipilimumab prevents this shutdown of anti-tumor Teff cell activity, prolonging the response. PD-1 expressed on lymphocytes interacts with its ligands PD-L1 or PD-L2 expressed on cancer cells or tumor-associated macrophages (TAMs), promoting Teff cell exhaustion. Nivolumab and pembrolizumab interfere with this interaction, again extending Teff cell effectiveness. ICB is considered to be a great clinical success and is now approved for treatment of metastatic melanoma and tumors with genomic instability (e.g., colorectal carcinoma) (Hargadon et al., 2018Hargadon K.M. Johnson C.E. Williams C.J. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors.Int. Immunopharmacol. 2018; 62: 29-39Crossref PubMed Scopus (155) Google Scholar). Indirect strategies targeting tumor cell metabolism aim to increase nutrient availability to immune cells, reduce production of immunosuppressive metabolites, and decrease acidity and hypoxia in the TME. Inhibiting tumor cell glycolysis directly or indirectly, either by PD-L1 blockade or mTORC1 inhibition, reduces glucose consumption and lactate production. Lactate production can also be directly targeted by inhibition of LDHA. Blocking enzymes such as IDO, Arg1, and glutaminase in cancer cells decreases amino acid depletion in the TME, although inhibition of IDO and COX interferes with the production of immunosuppressive molecules, such as kynurenines and prostaglandins, respectively. Kynurenines can also be directly inhibited by kynureninases. Glutamine antagonists decrease glutamine consumption by tumor cells and inhibit tumor metabolism. Pharmacological inhibition of the ETC in cancer cells can increase oxygen availability and reduce hypoxia. These strategies can be applied in addition to existing anti-cancer therapies, such as radiotherapy and chemotherapy. Direct strategies targeting immunometabolism aim to increase the fitness of immune cells and boost their anti-tumor activity. Inhibition of glycolysis or promotion of FAO in T cells as well as provision of exogenous arginine favor a memory phenotype with high anti-tumor activity. Also, glutamine antagonists favor a T cell memory phenotype by inducing metabolic reprogramming. 4-1BB co-stimulation can improve T cell proliferation and persistence. Inhibition of adenosine or ROS signaling through A2AR or ROS scavengers, respectively, reduces the immunosuppressive effects of these molecules on T cells. Blocking CTLA-4, IDO, COX, or Arg1 inhibits Treg cell formation and thus renders the TME less suppressive. In NK cells, inhibiting GSK3 prevents Myc degradation and increases NK effector functions. Cytokine stimulation of NK cells in vitro confers a memory phenotype with increased persistence after adoptive cell transfer. In macrophages, inhibition of CSF1R promotes the accumulation of pro-inflammatory macrophages in the TME. To inhibit the suppressive capacity of MDSCs, IDO inhibition, epigenetic modulation, and inhibition of fatty acid metabolism through CPT1 blockade have been proposed. In DCs, lipid metabolism is targeted because lipid accumulation impairs DC function. CPT1 and FAS inhibition as well as application of siRNA against the IRE1α-XBP1 signaling pathway can achieve this goal. Genetic ablation of Hif1α or inhibiting mTOR and Arg1 also reduce the suppressive phenotype of DCs in the TME. For B cells, CD40-mediated activation increases their capacity to activate cytotoxic T cells. Inhibition of enzymes promoting Breg cell differentiation, such as ALOX5, may decrease Breg cell frequencies in the TME. All these strategies can be applied in combination with ICB mediated by anti-CTLA or anti-PD-1 for T cells or anti-NKG2A for NK cells. A2AR, adenosine receptor; AKT, protein kinase B; ALOX5, arachidonate 5-lipoxygenase; Arg1, arginase 1; CPT1, carnitine palmitoyl transferase 1; CSF1, colony stimulating factor 1; CSF1R, colony stimulating factor 1 receptor; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; GSK3, glycogen synthase kinase 3; Hif1α, hypoxia inducible factor 1 α; IRE1α, inositol requiring kinase enzyme 1α; LDHA, lactate dehydrogenase; MDSC, myeloid-derived suppressor cells; mTORC1, mammalian target of rapamycin complex 1; NK, natural killer; O2, oxygen; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; PGE2, prostaglandin E2; PI3Kγ, phosphatidylinositol 3-kinase γ; siRNA, small interference RNA; XBP1, X-box binding protein 1. ACT of T cells most often involves isolating autologous or allogenic T cells, improving their anti-tumor capacity, expanding their numbers in culture, and transferring them back to the patient. To increase ACT efficiency, engineered T cell receptors (TCRs) are created to direct T cells to a specific antigen and optimize their affinity (Rosenberg et al., 2008Rosenberg S.A. Restifo N.P. Yang J.C. Morgan R.A. Dudley M.E. Adoptive cell transfer: a clinical path to effective cancer immunotherapy.Nat. Rev. Cancer. 2008; 8: 299-308Crossref PubMed Scopus (1023) Google Scholar). The latest form of ACT is named “chimeric antigen receptor” (CAR) T cell therapy, in which the transferred T cells are engineered to express artificial antigen-binding receptors composed of an antigen-recognition site, a transmembrane region, and one or more co-stimulatory domains. CARs are histocompatibility leukocyte antigen (HLA) independent and circumvent tumor escape mechanisms. CAR T cell therapy has proven very effective against B cell malignancies, such as recurrent acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) (Hartmann et al., 2017Hartmann J. Schüßler-Lenz M. Bondanza A. 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A major challenge with both ICB and ACT is the eventual development of T cell exhaustion and senescence, which prevent long-term Teff cell function and memory T cell development. Improving T cell fitness and longevity in the TME by metabolic stabilization could overcome these limitations, a goal that has prompted much recent basic research on T cell metabolism and its regulation. The activation and differentiation of T cell subsets are highly dependent on metabolic status. Naive T cells are quiescent and produce ATP primarily by mitochondrial OXPHOS. Upon TCR engagement and co-stimulation, newly activated T cells undergo metabolic remodeling and switch to aerobic glycolysis, which produces ATP faster and drives macromolecule synthesis. Activated CD4+ T cells differentiate into T helper cells, such as Th1, Th2, and Th17 cells, as well as Treg cells. Each subset requires distinct metabolic pathways to execute its functions. Both CD4+ Th cells and CD8+ Teff cells rely on glycolysis, express Glut1, and depend on mammalian target of rapamycin (mTOR) signaling to sustain their metabolic activity. In contrast, Treg cells express only low levels of Glut1, depend on fatty acid oxidation (FAO) (Macintyre et al., 2014Macintyre A.N. Gerriets V.A. Nichols A.G. Michalek R.D. Rudolph M.C. Deoliveira D. Anderson S.M. Abel E.D. Chen B.J. Hale L.P. Rathmell J.C. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function.Cell Metab. 2014; 20: 61-72Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar; Michalek et al., 2011Michalek R.D. Gerriets V.A. Jacobs S.R. Macintyre A.N. MacIver N.J. Mason E.F. Sullivan S.A. Nichols A.G. Rathmell J.C. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets.J. 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Buck M.D. Curtis J.D. Chang C.H. Smith A.M. Ai T. Faubert B. et al.CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability.Proc. Natl. Acad. Sci. USA. 2013; 110: 14336-14341Crossref PubMed Scopus (240) Google Scholar). The metabolic status of all these T cell subsets is crucial for their various anti-tumor functions, and it is becoming evident that the TME itself has a great influence on T cell metabolism, differentiation, and function. The modulation of various metabolites in the TME to boost anti-tumor responses is addressed in the next sections. The voracious consumption of glucose by cancer cells restricts its availability to normal cells in the TME. Using a sarcoma model, Chang et al., 2015Chang C.H. Qiu J. O’Sullivan D. Buck M.D. Noguchi T. Curtis J.D. Chen Q. Gindin M. Gubin M.M. van der Windt G.J. et al.Metabolic competition in the tumor microenvironment is a driver of cancer progression.Cell. 2015; 162: 1229-1241Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar showed that excessive glucose uptake by tumor cells decreased the anti-cancer activity of tumor-infiltrating lymphocytes (TILs) in a manner linked to reductions in mTOR activity, glycolytic capacity, and interferon γ (IFNγ) production. In a glucose-deprived setting, CD8+ T cells express lower levels of the essential anti-tumor effector molecules perforin and granzymes B and C (Cham et al., 2008Cham C.M. Driessens G. O’Keefe J.P. Gajewski T.F. Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells.Eur. J. Immunol. 2008; 38: 2438-2450Crossref PubMed Scopus (160) Google Scholar). Glucose restriction in the TME can induce T cell anergy or even apoptosis through the Noxa/Mcl-1 axis (Alves et al., 2006Alves N.L. Derks I.A. Berk E. Spijker R. van Lier R.A. Eldering E. The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells.Immunity. 2006; 24: 703-716Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar; Zheng et al., 2009Zheng Y. Delgoffe G.M. Meyer C.F. Chan W. Powell J.D. Anergic T cells are metabolically anergic.J. Immunol. 2009; 183: 6095-6101Crossref PubMed Scopus (157) Google Scholar). From a therapeutic perspective, increasing glucose availability in the TME can restore IFNγ production by TILs. By using ICB against PD-L1 on tumor cells, mTOR signaling is inhibited within these cells and their glycolytic turnover is reduced. Anti-tumor Teff cells are then able to increase their glucose uptake and extend their response (Chang et al., 2015Chang C.H. Qiu J. O’Sullivan D. Buck M.D. Noguchi T. Curtis J.D. Chen Q. Gindin M. Gubin M.M. van der Windt G.J. et al.Metabolic competition in the tumor microenvironment is a driver of cancer progression.Cell. 2015; 162: 1229-1241Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar). In addition, to improve their function in low-glucose TME, Ho and colleagues (Ho et al., 2015Ho P.-C. Bihuniak J.D. Macintyre A.N. Staron M. Liu X. Amezquita R. Tsui Y.C. Cui G. Micevic G. Perales J.C. et al.Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses.Cell. 2015; 162: 1217-1228Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar) transferred genetically engineered tumor-specific CD4+ and CD8+ T cells to overexpress phosphoenolpyruvate carboxykinase (PCK1). PCK1 allows the accumulation of the glycolytic metabolite phosphoenolpyruvate (PEP), which sustains nuclear factor of activated T cells (NFAT) signaling and consequent activation. ACT of these metabolic-modulated T cells to tumor-bearing mice decreased tumor growth and improved survival (Ho et al., 2015Ho P.-C. Bihuniak J.D. Macintyre A.N. Staron M. Liu X. Amezquita R. Tsui Y.C. Cui G. Micevic G. Perales J.C. et al.Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses.Cell. 2015; 162: 1217-1228Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar). On the other hand, in ACT, blocking glucose metabolism can have the opposite effect. Treatment of CD8+ T cells during ex vivo expansion with 2-deoxyglucose (2-DG), a glucose analog that impedes glycolysis, enhances the generation of memory cells and anti-tumor function after transfer (Sukumar et al., 2013Sukumar M. Liu J. Ji Y. Subramanian M. Crompton J.G. Yu Z. Roychoudhuri R. Palmer D.C. Muranski P. Karoly E.D. et al.Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function.J. Clin. Invest. 2013; 123: 4479-4488Crossref PubMed Scopus (353) Google Scholar). Glucose availability also influences mTOR signaling and Treg cell differentiation (Delgoffe et al., 2009Delgoffe G.M. Kole T.P. Zheng Y. Zarek P.E. Matthews K.L. Xiao B. Worley P.F. Kozma S.C. Powell J.D. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment.Immunity. 2009; 30: 832-844Abstract Full Text Full Text PDF PubMed Scopus (717) Google Scholar). High numbers of Treg cells are associated with poor prognosis in many cancers, and Treg cell depletion promo