Metabolic checkpoints in immune cell reprogramming: rewiring immunometabolism for cancer therapy

Abstract

Immune cell metabolism plays a pivotal role in regulating cellular proliferation, differentiation, and functional responses, collectively shaping immune responses within the tumor microenvironment (TME). Recent advancements increasingly highlight diverse metabolic phenotypes of immune cells and their complex interplay with tumor dynamics. Immune cell metabolism exhibits remarkable plasticity, enabling metabolic networks to finely tune immune cell behaviors in response to external stimuli. Furthermore, a strong correlation between metabolic profiles and immune cell fate, activation, and function has been repeatedly delineated in immunometabolism. Consequently, targeting the metabolic networks, referred to as metabolic checkpoints, to reprogram immune cell phenotypes and bolster antitumor immunity holds significant promise for clinical translation. This review summarizes the latest developments in multifaceted metabolic checkpoints, with a focus on how metabolic checkpoints modulate immunological consequences and cancer progression. Lastly, potential strategies for targeting metabolic checkpoints are explored to inspire innovative approaches in immunotherapy.

Keywords: Cancer immunotherapy; Immune cells; Metabolic checkpoints; Metabolic reprogramming; T cell; Tumor microenvironment.

Fig. 1

Metabolic pressure in the TME. Metabolic pathways are usually dysregulated in the TME, consistently imposing tremendous metabolic pressure on both cancer cells and various immune cells. Nutrient deprivation, waste accumulation, hypoxia, oxidative stress, and increased acidity are driving forces that contribute to an immunosuppressive milieu. Nevertheless, cancer cells, with remarked metabolic plasticity, outcompete immune cells in the metabolic competition. Abbreviations: NK cell, natural killer cell; DC cell, dendritic cell; ROS, reactive oxygen species

Fig. 2

Metabolic networks of CD8⁺ T cells in the TME. In interaction with numerous cell types within the TME, CD8 + T cells consistently suffer from the nutrient-depleted and toxic metabolite-accumulating environment. T cells exhibit reprogrammed metabolism, whereas the metabolic network tightly controls their immune functions. Upon activation, CD8⁺ T cells undergo extensive metabolic reprogramming to support their effector functions. A shift toward glycolysis enhances effector activity, while the branching of HBP facilitates protein O-GlcNAcylation, further promoting T cell function. Elevated acetyl-CoA levels, resulting from enhanced glycolysis and TCA cycle activity, contribute to improved CTL metabolic fitness and functionality. In the nutrient-deprived TME, deficiencies in arginine, glutamine, leucine, methionine, and other key nutrients collectively impair CD8⁺ T cell proliferation and effector function. mTORC1 activity, regulated by glucose, amino acids, oxygen, and growth factors, plays a central role in coordinating cellular metabolism and growth. Conversely, FAO driven by CD36-mediated lipid uptake promotes CD8⁺ T cell dysfunction, highlighting a distinct metabolic state associated with T cell exhaustion. Consistent with this, a variety of metabolic checkpoints—including metabolites (e.g., glucose, lactate, glutamine, oxygen), enzymes (e.g., HK2, LDHA, FASN), and transcription factors (e.g., MYC, HIF-1α, PPARα)—collectively orchestrate the metabolic network of CD8⁺ T cells. Abbreviations: LDHA, lactate dehydrogenase A; HK2, hexokinase 2; HIF, hypoxia-inducible factor; HBP, hexosamine biosynthesis pathway; TCA circle, tricarboxylic acid cycle; α-KG, α-ketoglutarate; ACLY, adenosine 5'-triphosphate citrate lyase; FASN, fatty acid synthase; ACC1, acetyl-CoA carboxylase 1; AMPK, AMP-activated protein kinase; FAO, fatty acid oxidation; PPAR, peroxisome proliferator-activated receptor; ER stress, endoplasmic reticulum stress; SLC family, solute carrier family; mTORC1, mechanistic target of rapamycin complex 1; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; MSDC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage, Treg, regulatory T cell

Fig. 3

Suppression of immunometabolism on CD8 + T cells. In the immunosuppressive TME, multiple immunoregulatory cells—including TAMs, MDSCs, and Tregs—exert profound metabolic control over CTLs, thereby dampening antitumor immunity. For instance, arginine metabolism in TAMs and MDSCs actively molds the immunosuppressive milieu in the TME, as Arg1-mediated arginine depletion contributes to Teff dysfunction. The upregulation of IDO in TAMs and kynurenine production significantly impairs T cells. Tregs rely heavily on lipid metabolism for suppressive function, where CD36, AMPK, CPT1a, the PI3K-AKT-mTOR axis, etc. serve as key regulators. Of note, the therapeutic blockade of Arg1, IDO, and FAO has shown promising potential in reversing immune suppression within the TME. Abbreviations: TAM, tumor-associated macrophage; PPAR, peroxisome proliferator-activated receptor; LXR, liver X receptor; PPP, pentose phosphate pathway; TCA circle, tricarboxylic acid cycle; FAO, fatty acid oxidation; NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; Arg1, arginase 1; MDSC, myeloid-derived suppressor cell; SCFAs, short-chain fatty acids; FFAR2, free fatty acid receptor 2; PPAR-γ, peroxisome proliferator-activated receptor γ, IDO, indoleamine 2,3-dioxygenase; iNOS, inducible nitric oxide synthase; Treg, regulatory T cell; mTORC1, mechanistic target of rapamycin complex 1; HIF, hypoxia-inducible factor; MCT1, monocarboxylate transporter 1

Fig. 4

Metabolic profiles of immune cells. Immune cells adopt distinct metabolic programs in response to environmental cues. During tumor progression, the immunometabolic landscape of the TME dynamically reprograms immune cell metabolism, contributing to functional reprogramming and immune dysregulation. Abbreviations: TME, tumor microenvironment; DC, dendritic cell; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell; OXPHOS, oxidative phosphorylation; HIF, hypoxia-inducible factor; ROS, reactive oxygen species; TCA circle: tricarboxylic acid cycle; iNOS, inducible nitric oxide synthase; mTORC1, mechanistic target of rapamycin complex 1; FAO, fatty acid oxidation; IDO, indoleamine 2,3-dioxygenase; Arg1, arginase 1; PPP, pentose phosphate pathway; AMPK, AMP-activated protein kinase; TCA circle, tricarboxylic acid cycle; SREBP, sterol regulatory element-binding protein