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) |
|
| 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) |