Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Jul 10;13(1):66.
doi: 10.1186/s40164-024-00535-1.

Fueling CARs: metabolic strategies to enhance CAR T-cell therapy

Arne Van der Vreken  1 , Karin Vanderkerken  1 , Elke De Bruyne  1 , Kim De Veirman  1 , Karine Breckpot  2 , Eline Menu  3
Affiliations
Review

Fueling CARs: metabolic strategies to enhance CAR T-cell therapy

Arne Van der Vreken et al. Exp Hematol Oncol. .

Abstract

CAR T cells are widely applied for relapsed hematological cancer patients. With six approved cell therapies, for Multiple Myeloma and other B-cell malignancies, new insights emerge. Profound evidence shows that patients who fail CAR T-cell therapy have, aside from antigen escape, a more glycolytic and weakened metabolism in their CAR T cells, accompanied by a short lifespan. Recent advances show that CAR T cells can be metabolically engineered towards oxidative phosphorylation, which increases their longevity via epigenetic and phenotypical changes. In this review we elucidate various strategies to rewire their metabolism, including the design of the CAR construct, co-stimulus choice, genetic modifications of metabolic genes, and pharmacological interventions. We discuss their potential to enhance CAR T-cell functioning and persistence through memory imprinting, thereby improving outcomes. Furthermore, we link the pharmacological treatments with their anti-cancer properties in hematological malignancies to ultimately suggest novel combination strategies.

Keywords: CAR T cells; Co-stimulus; Drug repurposing; Metabolism; Mitochondria.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Signal transduction and its relation to metabolism in effector and memory T cells. Optimal effector T-cell signaling is induced by a combination of signals from an activated T-cell receptor (TCR), CD28 co-stimulation, and cytokines such as IL-2. Together, these signals activate the PI3K/Akt/mTORC1 pathway, leading to the activation of glycolytic genes. Activated Akt inhibits FOXO1. In memory T cells, mTORC1 signaling is downregulated by AMPK and cues such as IL-15R signaling. The reduced mTORC1/Akt activity results in the activation of the transcription factor FOXO1, which induces a memory gene signature. Memory T cells have an increased mitochondrial mass with more tubular cristae, facilitating close proximity between the different complexes of the electron transport chain. In contrast, effector T cells exhibit mitochondria with loose cristae and increased physical distance between the complexes of the electron transport chain. (PI3K: Phosphatidylinositol 3-kinases, PGC-1α: Peroxisome proliferator-activated receptor-gamma coactivator 1alpha, mTORC1: mammalian target of rapamycin complex 1, HIF1α: hypoxia-inducible factor 1-alpha, ACC2: acetyl-coenzyme A (CoA) carboxylase A, AMPK: adenosine monophosphate-activated protein kinase, FAO: fatty acid oxidation, TCR: T-cell receptor, IL-2R: interleukin-2 receptor, IL-15R: interleukin-15 receptor, FOXO1: Forkhead box protein O1, Akt: protein Kinase B). Created with Biorender.com
Fig. 2
Fig. 2
(Metabolic) effects of different co-stimuli. Each co-stimulatory domain in CAR T cells engages unique immunometabolic signaling pathways, leading to distinct phenotypes. Second-generation CAR T cells incorporating CD28 domains promote effector differentiation and predominantly rely on glycolysis. Co-stimulatory domains such as 4-1BB, OX-40, and BAFF-R progressively enhance NF-κB signaling, support mitochondrial metabolism, and foster memory cell imprinting. (TCR: T-cell receptor, OXPHOS: oxidative phosphorylation, BAFF-R = B-cell activating factor receptor, Nuclear factor kappa-light-chain-enhancer of activated B-cells). Created with Biorender.com
Fig. 3
Fig. 3
Metabolic targets to enhance CAR T-cell function and memory formation. Inhibition of targets are indicated in red, overexpression and stimulators in green. The PI3K/Akt/mTORC1 signaling pathway promotes a glycolytic gene signature, facilitating rapid energy production. Inhibition (e.g. via pretreatment of CAR T cells) of this pathway or other glycolytic proteins such as LDHA and MCTs results to increased memory formation in CAR T cells. Conversely, CAR T-cell function can be improved through several mechanisms. These include enhancing mitochondrial biogenesis via bezafibrate, overexpression of PGC-1α, or knockout of Regnase-1; preventing reductive carboxylation through IDH2 inhibition; and stimulating mitochondrial oxidation by overexpressing amino acid transporters, urea cycle enzymes, TCA cycle enzymes or inhibiting MPC. Similar beneficial effects are observed by stimulating AMPK signaling using metformin. (OE: overexpression, KO: knock-out, shRNA: short hairpin RNA, PIP2: Phosphatidylinositol(4,5)-bisphosphate, PIP3: Phosphatidylinositol(3,4,5)-trisphosphate, PI3K: Phosphatidylinositol 3-kinases, PGC-1α : Peroxisome proliferator-activated receptor-gamma coactivator 1alpha, MCT: monocarboxylate transporter, LDHA: Lactate dehydrogenase A, GLUT1: Glucose transporter 1, MPC: mitochondrial pyruvate carrier, ETC: electron transport chain, α-KG: alpha-ketoglutarate, IDH2: Isocitrate dehydrogenase 2, P5C: pyrroline-5-carboxylate, OTC: ornithine transcarbamylase, ASS: Argininosuccinate synthase or synthetase, mAb: monoclonal antibody, PD-1: programmed death-1 CTLA-4: Cytotoxic T-lymphocyte-associated protein 4, Cyt C: cytochrome C, ADP: adenosinediphosphate, ATP: adenosinetriphosphate). Created with Biorender.com
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Guzman G, Reed MR, Bielamowicz K, Koss B, Rodriguez A. CAR-T therapies in solid tumors: opportunities and challenges. Curr Oncol Rep. 2023;25(5):479–89. doi: 10.1007/s11912-023-01380-x. - DOI - PMC - PubMed
    1. Schett G, Mackensen A, Mougiakakos D. CAR T-cell therapy in autoimmune diseases. Lancet. 2023;402(10416):2034–44. doi: 10.1016/S0140-6736(23)01126-1. - DOI - PubMed
    1. Guan M, Lim L, Holguin L, Han T, Vyas V, Urak R, et al. Pre-clinical data supporting immunotherapy for HIV using CMV-HIV-specific CAR T cells with CMV vaccine. Mol Ther Methods Clin Dev. 2022;25:344–59. doi: 10.1016/j.omtm.2022.04.007. - DOI - PMC - PubMed
    1. Dai H, Zhu C, Huai Q, Xu W, Zhu J, Zhang X et al. Chimeric antigen receptor-modified macrophages ameliorate liver fibrosis in preclinical models. J Hepatol. 2024. - PubMed
    1. Jacobson CA, Chavez JC, Sehgal AR, William BM, Munoz J, Salles G, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23(1):91–103. doi: 10.1016/S1470-2045(21)00591-X. - DOI - PubMed

LinkOut - more resources