From: Lipid metabolism in tumor-infiltrating regulatory T cells: perspective to precision immunotherapy
Molecule | Metabolic transition | Mechanism | Function |
---|---|---|---|
α-KG | Enhances OXPHOS, promotes lipid storage | Up-regulates mitochondrial complex enzymes, promotes DNA methylation | Significantly attenuates Tregs differentiation and increases inflammatory cytokines [128] |
FABPs | Maintain lipid metabolism and OXPHOS | Affects the integrity and function of mitochondria | Inhibition of FABP5 promotes Tregs suppressive function [32] |
TKT | Stabilizes glycolysis, inhibits excessive fatty acid and amino acid catabolism | Maintains mitochondrial fitness | Maintains the suppressive function [132] |
TFEB | Maintains mitochondrial function, promotes lipid metabolism | - | Increases Tregs number and suppressive function [98] |
HIF-1α | Promotes glycolysis and lipid oxidation | Activates mTOR pathway; TME-related HIF1α activation prevents glucose from entering mitochondria and promotes FAO; Glycolysis drives Tregs migration | Under inflammatory conditions, HIF-1α is more prone to induce proinflammatory Teffs [67, 81, 82]; Enhances OXPHOS-dependent immunosuppression [79] Increases the number of TI-Tregs [79] |
HIF-2α | — | As an inhibitory target of HIF1α | Promotes Tregs function [82] |
TLR | Promotes glycolysis | Activates mTOR pathway, up-regulates Glut1 | Inhibits Tregs function [65] |
PTEN | Inhibits glycolysis | As an upstream inhibition target of PI3K | Inhibits the immune response induced by apoptotic tumor cell antigens and stabilizing Tregs [86] |
FOXO1 | Decreases glycolysis and oxidation rates, inhibits cholesterol synthesis | Activates AKT, inhibits IL-2 signaling dependent mTORC1 biosynthesis | Inhibits the proliferation of CD4+T cells [59] |
AMPK | Inhibits glycolysis | As an mTORC1 upstream inhibitor | Increases Tregs numbers [81] |
LKB1 | Preserves mitochondrial function and OXPHOS, maintains cholesterol homeostasis | Activates AMPK, promotes the mevalonate pathway and its gene expression | |
PP2A | Limits glycolysis | Inhibits mTORC1 | Maintains suppressive function [75] |
MTHFD2 | Maintains purine metabolism | Maintains mTORC1 activity | Promotes Tregs differentiation [91] |
SREBPs | Promote lipid and cholesterol synthesis | Activate FASN-mediated de novo fat synthesis, and inhibit mTOR signaling | Promote Tregs maturation and up-regulate the expression of PD-1 [33] |
CD36 | Promote lipid oxidation | Transfers LCFAs, activates PPAR-β pathway | Promotes the adaptation to TME and enhances its inhibitory function [46] |
Foxp3 | Inhibits glycolysis, enhances OXPHOS, and increases nicotinamide adenine dinucleotide oxidation | Inhibits mTOR and Myc | Promotes Tregs adaptation to TME and resists lactate-mediated inhibition of T cell function and proliferation [95] |
SEC31A | — | Interacts with Sect. 13, activates mTORC1 | Maintains the suppressive function [85] |
SWI/SNF complex | — | Down-regulate amino acid sensor CASTOR1 expression, increases mTORC1 activity | Maintain the suppressive function [85] |
ccdc101 | — | As an inhibitor of mTORC1, limits the expression of glucose and amino acid transporters | Maintains the suppressive function [85] |
Atg7/Atg5 | Reduce glycolysis | Stabilize mTORC1 and c-Myc | Maintain autophagy, promote the expression of Foxp3 and suppressive function [90] |
KLF10 | Promotes glycolysis and mitochondrial respiration | Maintains the mTOR pathway | |
G9a | Inhibits OXPHOS, enhances cholesterol synthesis | Inhibition of G9a promotes SREBP expression and the mevalonate pathway | Enhances immunosuppressive capacity [70] |