Table 2 Metabolic targeted drugs and their mechanisms of action
From: Lipid metabolism in tumor-infiltrating regulatory T cells: perspective to precision immunotherapy
Target | Drug | Mechanism | Physiological effects |
|---|---|---|---|
SREBP1 | Fatostatin [108] | Inhibits lipid synthesis and mitochondrial integrity in TAMs | Attenuates Tregs-dependent TAMs |
EP2\EP4 | SC-560, celecoxib, AS3385282-00 (EP2i), ASP7657 (EP4i) [126] | Inhibit PGE2-EP2/EP4 signaling pathway | Reduce TI-Tregs enrichment and activation |
CD70 | Anti-cd70 monoclonal antibody [112] | Inhibits CD70-CD27 dependent lipid signaling network | Reduces TI-Tregs number and attenuates immunosuppression function |
S1P1 | Selectively activates Akt-mTOR kinase, and promotes glycolysis | Blocks the differentiation of Tregs and inhibits the function of mature Tregs | |
IVA phospholipase A2 | MAFP [110] | Activates MAPK, stabilizes Teffs lipids metabolism | Attenuates Treg-promoted Teffs senescence |
PD-1 | Activates mTOR signaling pathway, attenuates FAS and cholesterol synthesis; Inhibits FAO, and reduces mitochondrial number | Attenuates TI-Tregs function | |
HMGCR | Adenylate [64] | Inhibits downstream GSK3β, β-catenin axis, and PD-1 | Weakens suppressive function |
Simvastatin [33] | Inhibits the mevalonate pathway and activates PI3K | Detrimental to the stability of Tregs | |
GGTTI | GGTI [33] | Inhibits mevalonate pathway and activates PI4K | Detrimental to the stability of Tregs |
Farnesyl transferase | FTI [33] | Inhibits mevalonate pathway and activates PI5K | Detrimental to the stability of Tregs |
OXPHOS | Oligomycin [125] | Inhibits OXPHOS | Decreases Foxp3 expression and IL-10 production |
CD36 | Anti-CD36 monoclonal antibody [46] | Inhibits PPAR-β pathway, reduces lipid metabolism | Reduces TI-Tregs aggregation and function |
LDH | GSK 2,837,808 A [95] | Inhibits LDL-mediated NAD consumption | Promotes the survival of Teffs and Tconv, antagonizes the effect of Tregs |
CTLA-4 | Ipilimumab [125] | Inhibits lipid metabolism, enhances glycolysis | Weakens suppressive capacity and the stability of TI-Tregs |
HIF-1α | Inhibits HIF-1α-mediated glycolysis that promotes Tregs migration | Disturbs TI-Tregs accumulation | |
PIP4K | NIH-12,848 [129] | Inhibits PI3K, mTORC1/S6 and MAPK pathways | Inhibits Foxp3 expression, impairs proliferation, and induces cell death |
PTEN | VO-Ohpic [86] | Relieves the inhibition of the mTOR pathway | Promotes the conversion of Tregs to inflammatory phenotype |
ACC | TOFA [11] | Reduces lipid synthesis | Inhibits proliferation and function, especially KLRG1+CD103+Tregs with high inhibitory capacity |
PI3K | Wortmannin、CAL-101 [129] | Inhibits PI3K-AKT-mTOR pathway | Reduces differentiation and number |
AKT | Triciribine [133] | Inhibits mTOR signaling pathway and TCR signaling | Detrimental to proliferation |
mTORC1 | Inhibits mTOR signaling pathway | Reduces Tregs numbers | |
TCA | α-KG [112] | Promotes the methylation of Foxp3 promoter, CNS1 region | Inhibits differentiation |