Table 1 Metabolic regulators of Tregs

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

Maintains Tregs number and function [77, 88, 89]

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

Maintains chemotaxis [76, 84]

G9a

Inhibits OXPHOS, enhances cholesterol synthesis

Inhibition of G9a promotes SREBP expression and the mevalonate pathway

Enhances immunosuppressive capacity [70]