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Review Open Access

Mechanisms of T‑cell metabolic reprogramming in the microenvironment of acute myeloid leukemia and its therapeutic potential (Review)

  • Authors:
    • Yanhong Luo
    • Jie Luo
    • Min Yang
    • Xueya Zhao
  • View Affiliations / Copyright

    Affiliations: Department of Hematology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China, Bishan Hospital of Chongqing Medical University, Chongqing 402760, P.R. China, Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, P.R. China
    Copyright: © Luo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 455
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    Published online on: July 22, 2025
       https://doi.org/10.3892/ol.2025.15201
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Abstract

Acute myeloid leukemia (AML) is an aggressive hematological malignancy that is often resistant to conventional therapies. The present narrative review discusses on the role of T cell metabolic reprogramming in the AML tumor microenvironment (TME), which markedly impacts the effectiveness of immunotherapy. The TME of AML, influenced by factors such as high lactic acid (LA) levels, hypoxia and nutrient competition, hampers T cell functions such as glycolysis, lipid metabolism and amino acid metabolism, leading to impaired T cell proliferation and antitumor response. Metabolic waste products, including LA and adenosine, further contribute to the immunosuppressive environment. T cell exhaustion, induced by nutrient deprivation and metabolic dysregulation, serves a key role in the failure of immune responses. Moreover, strategies to modulate T cell metabolism, such as targeting glycolysis and fatty acid oxidation, show promise in enhancing immunotherapy outcomes. The current review also highlights emerging technologies, such as single‑cell metabolomics and CRISPR screening, which are critical for identifying metabolic targets and advancing personalized therapies. Despite challenges in translating these findings to clinical settings, understanding T cell metabolism in the AML TME offers new therapeutic avenues for improving patient outcomes.
View Figures

Figure 1

Acute myeloid leukemia tumor
microenvironment is characterized by high lactic acid levels, which
create an acidic milieu that impairs T cell function. Lactic acid
inhibits perforin and granzyme B, essential for T cell-mediated
tumor cell killing, and reduces the secretion of cytokines such as
IL-2 and IFN-γ, critical for CD4+ T cell proliferation.
Lactic acid accumulation in Tregs is facilitated by MCT1,
activating NFAT1 signaling and upregulating PD-1, enhancing
Treg-mediated immunosuppression. IFN-γ, interferon-γ; Treg,
regulatory T cell; MCT1, monocarboxylate transporter 1; NFAT1,
nuclear factor of activated T cells 1; PD-1, programmed
death-1.

Figure 2

Adenosine binds to receptors on Teff,
Treg, and APCs, suppressing Teff activation, proliferation and
cytokine secretion whilst enhancing Treg-mediated immunoregulation.
This signaling pathway also decreases the production of IL-12 and
increases IL-10, further weakening the antitumor immune response.
Treg, regulatory T cell; Teff, Tregs suppress effector T cell; APC,
adenomatous polyposis coli.

Figure 3

mTOR enhances glucose uptake and
glycolysis in CD4+ T cells by increasing GLUT1
expression and regulating the IRS1/PI3K/AKT pathway. This promotes
glycogen synthesis, T cell proliferation and activation, favoring
Th1/Th17 differentiation whilst reducing Treg generation.
Inhibition of mTOR impairs glycolysis and CD4+ T cell
activation. GLUT1, glucose transporter 1; IRS1, insulin receptor
substrate 1; Treg, regulatory T cell; AMPK, AMP-activated protein
kinase; Th, Helper T cell.

Figure 4

As an mTOR inhibitor, AMPK suppresses
mTOR activity via metformin, reducing glycolysis and promoting Treg
generation whilst suppressing Th1/Th17 differentiation. AMPK also
upregulates CPT1, enhancing FAO and supporting T cell metabolic
reprogramming. Additionally, HIF-1α promotes Treg migration by
upregulating glycolysis and FAO. AMPK, AMP-activated protein
kinase; Th, Helper T cell; Treg, regulatory T cell; CPT1, carnitine
O-palmitoyl transferase 1; HIF-1α, hypoxia-inducible factor 1α;
LDHA, lactate dehydrogenase A; FAO, fatty acid oxidation; Tm,
memory T cell.
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Copy and paste a formatted citation
Spandidos Publications style
Luo Y, Luo J, Yang M and Zhao X: Mechanisms of T‑cell metabolic reprogramming in the microenvironment of acute myeloid leukemia and its therapeutic potential (Review). Oncol Lett 30: 455, 2025.
APA
Luo, Y., Luo, J., Yang, M., & Zhao, X. (2025). Mechanisms of T‑cell metabolic reprogramming in the microenvironment of acute myeloid leukemia and its therapeutic potential (Review). Oncology Letters, 30, 455. https://doi.org/10.3892/ol.2025.15201
MLA
Luo, Y., Luo, J., Yang, M., Zhao, X."Mechanisms of T‑cell metabolic reprogramming in the microenvironment of acute myeloid leukemia and its therapeutic potential (Review)". Oncology Letters 30.4 (2025): 455.
Chicago
Luo, Y., Luo, J., Yang, M., Zhao, X."Mechanisms of T‑cell metabolic reprogramming in the microenvironment of acute myeloid leukemia and its therapeutic potential (Review)". Oncology Letters 30, no. 4 (2025): 455. https://doi.org/10.3892/ol.2025.15201
Copy and paste a formatted citation
x
Spandidos Publications style
Luo Y, Luo J, Yang M and Zhao X: Mechanisms of T‑cell metabolic reprogramming in the microenvironment of acute myeloid leukemia and its therapeutic potential (Review). Oncol Lett 30: 455, 2025.
APA
Luo, Y., Luo, J., Yang, M., & Zhao, X. (2025). Mechanisms of T‑cell metabolic reprogramming in the microenvironment of acute myeloid leukemia and its therapeutic potential (Review). Oncology Letters, 30, 455. https://doi.org/10.3892/ol.2025.15201
MLA
Luo, Y., Luo, J., Yang, M., Zhao, X."Mechanisms of T‑cell metabolic reprogramming in the microenvironment of acute myeloid leukemia and its therapeutic potential (Review)". Oncology Letters 30.4 (2025): 455.
Chicago
Luo, Y., Luo, J., Yang, M., Zhao, X."Mechanisms of T‑cell metabolic reprogramming in the microenvironment of acute myeloid leukemia and its therapeutic potential (Review)". Oncology Letters 30, no. 4 (2025): 455. https://doi.org/10.3892/ol.2025.15201
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