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Table 1 Targeting metabolic pathways and their regulators in intratumoral Tregs

From: Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity

Target Drug Mechanisms of action Effect on Tregs
Glycolysis 2-DG, 2-ME, galloflavin, dichloroacetate [89, 141,142,143] Inhibit glucose uptake and glycolysis Inhibit Treg suppression on Teff proliferation
TLR8 Poly-G3, ssRNA40 [141, 143] Act as TLR8 agonists; inhibit glucose uptake and glycolysis by disrupting the mTOR-HIF-1α axis Inhibit Treg suppression on Teff
mTOR Rapamycin, curcumin analog GO-Y030 [144, 178] Inhibit mTOR signal, glucose uptake, and glycolysis Inhibit Treg population and immune-suppressive ability
mTORC1 Metformin [179] Act as a mTORC1 agonist; induce metabolic change from OXPHOS to glycolysis Inhibit iTreg differentiation, especially terminally differentiated KLRG1+CD103+Treg cells
PTEN VO-Ohpic [124] Inhibit PTEN signal and stimulate PI3K-AKT axis Cause Treg instability and conversion into ex-Tregs as well as inhibit Treg suppressive function
PI3K Wortmannin [180] Inhibit PI3K, TCR, and Treg-specific signals Selectively inhibit Treg proliferation and function
Pan-PI3K Copanlisib [183] Undefined Decrease Treg cell infiltration
PI3K-β GSK2636771 [145] Inhibit PI3K-β signal and interfere with Treg lipid metabolism Decrease Treg cells
PI3K-δ Idelalisib (previously CAL-101, GS-1101), PI-3065, parsaclisib [181, 182, 184, 185] Inhibit PI3K-δ, AKT phosphorylation TCR and Treg-specific signals Reduce Treg number, differentiation, and function
AKT Triciribine [180] Inhibit AKT, TCR, and Treg-specific signals Selectively inhibit Treg proliferation and function
ACC TOFA [142] Inhibit ACC and FAS Inhibit Treg proliferation
CD36 A monoclonal antibody blocking CD36 [147] Inhibit FA transport, lipid metabolism as well as mitochondrial fitness and biogenesis Inhibit intratumoral Treg accumulation and suppression without systemic loss of Treg number and function
CPT1a Etomoxir [120] Inhibit CPT1a and FAO Decrease Treg number
PDH CPI-613 [178] Inhibit PDH; block the TCA cycle and mitochondria metabolism Decrease Tregs and Bregs
IDO1 Secondary sulfonamides (compound 5d), GDC-0919, epacadostat, NLG802 [41, 152, 154, 186] Inhibit IDO1-catalyzed kynurenine pathway Inhibit Treg differentiation and suppression
MCT-1 AZD3965 [25] Inhibit lactate uptake and its support to Treg function Selectively inhibit intratumoral Tregs without disturbing pTregs
L-lactate Curcumin analog GO-Y030 [144] Inhibit L-lactate production by melanoma cells Inhibit the support of extracellular lactate on Treg function
  1. 2-DG 2-deoxyglucose; 2-ME 2-mercaptoethanol; TLR Toll-like receptor; PTEN phosphatase and tensin homolog; TCR T cell receptor; ACC acetyl-CoA carboxylase; TOFA 5-tetradecyloxy-2-furoic acid; FAS fatty acid synthesis; CPT1 carnitine palmitoyltransferase-1; PDH pyruvate dehydrogenase; IDO indoleamine 2; 3-dioxygenase; MCT1 monocarboxylate transporter 1