Table 1.

The effect of metformin and its downstream factors on TME components

TME components	Key regulator / region	Regulatory mechanism	Disease	References
Chronic inflammation	TNF-γ, TNF-α, IL-6, and IL-17	Metformin down-regulates the level of chemokines and pro-inflammatory cytokines.	Multiple sclerosis	(41)
	TNF-α and IL-6	Metformin decreases the level of inflammatory cytokines by suppressing NF-κB signaling.	T2D, cardiovascular complications	(42, 43) (44, 45)
	ROS and IL-1β	Metformin decreases the level of inflammatory cytokines from LPS-activated macrophages by means of inhibition of mitochondrial complex I.	Inflammation	(46)
	TAM polarization	Metformin inhibit tumor growth by promoting M2-TAM polarization	Cancer	(47)
	MDSC chemotaxis	Metformin has anti-tumor effect by reducing MDSC accumulation in the TME via AMPK/DACH1/CXCL1 axis.	Cancer	(48)
Hypoxia	Hypoxia	Metformin reduces intratumoral hypoxia.	Cancer	(58)
	HIF-1α	Metformin suppresses accumulation of HIF-1α.	Cancer	(59, 60)
	Oxygen consumption	Metformin relieves intratumoral hypoxia, resulting in improving T-cell immunity in the TME.	Cancer	(61)
PD-L1 expression	PD-L1	Metformin-activated AMPK induces ERAD of PD-L1, resulting in enhanced CD8+ TIL activity.	Cancer	(11)
	PD-L1	Metformin improves cytotoxicity of CD8+ T-cell by reducing membrane-bound PD-L1 level.	Cancer	(68)
	PD-L1	Metformin treatment reverses PD-L1 level, which sensitizes PARPi-resistant cells to CTL.	Cancer	(69)
Metabolic reprogramming of T-cell	AMPK	Metformin does not only increase the multi-functionality of CD8+ CTL but also improve long-term memory immunity.	Cancer	(10)
	Oxidative metabolism	AMPK maintain consistent activity of CTL under glucose depletion.	Cancer	(76)
	Protein phosphatases	Genetic ablation of AMPKα1 in T-cell cause apoptosis of CD8+ CTL.	Cancer	(77)
	mTORC1	TSC2 KO mice generate highly glycolytic and potent effector CTL.	Cancer	(78)
	mTOR	Rapamycin treatment increases the population of CD8 + memory T-cells.	Virus infection	(82)