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

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.

Keywords: T cells; immunization; tumor immunology.

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.