Table 1 Targeting metabolic pathways and their regulators in intratumoral 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