Table 3.
Possible and rational therapies targeting MDSCs for pre-metastatic niche disruption after tumor resection
| Strategies | Drugs | Clinical trial | Mechanisms | Reference |
|---|---|---|---|---|
| Anti-surgical stress | β-blockade (Propranolol) | NCT03152786/NCT02013492 | Block the β2-AR signal in MDSCs | 109 |
| COX-2 inhibitor (Celecoxib, Etodolac) | NCT03896113/NCT03864575/NCT03838029 | Disruption of the COX-2/PGE-2 signals; reducing MDSC recruitment and differentiation, repressing MDSC-associated suppressive factors such as Arg-1 and ROS production | 81 | |
| Anti-DAMPs | Anti-HMGB 1 antibody | Preclinical | Ameliorated the trauma-induced attenuated T-cell responses and accumulation of MDSCs in the spleens seen 2 days after injury | 44 |
| S100A8/A9 neutralizing antibody | Preclinical | Neutralizing extracellular S100A8/A9 | 119 | |
| Anti-inflammatory signals | NF-κB inhibitor (BAY11-7082) | Preclinical | Inhibiting NF-κB mediated CXCL1, CXCL2 and CXCL5 production, that reduce the chemotaxis of MDSCs; Inhibition NLRP3 inflammasome activation and the increased pyroptosis | 124 |
| NLRP3 inhibitor (MCC950/CY-09/OLT1177/Tranilast/Oridonin) | Preclinical | Inhibition NLRP3 inflammasome activation and the following IL-1β secretion | 121 | |
| IL-1β (Anakinra) | NCT02780583/NCT04359784 | Inhibit the IL-1β inducing CCL5, CXCL12, CCL2, and CXCL5 expression | 50 | |
| Epigenetic drugs | HDAC (Entinostat) | NCT01207726/NCT03501381/NCT03552380 | Downregulating CCR2 and CXCR2 expression; promoting MDSC differentiation into a more-interstitial macrophage-like phenotype | 5 |
| DMNT (5-azacytidine) | NCT01207726/NCT03709550 | |||
| Depletion of MDSCs | Chemotherapy (Gemcitabine/5-FU) | NCT04331626/NCT01803152/NCT02090101 | Depletes G-MDSCs, M-MDSCs, macrophages, and eosinophils | 142 |
| TKI(Pazopanib/Bevacizumab) | NCT01832259/NCT01218048 | Blockade of VEGF and c-KIT signaling; inhibit STAT3 | 129 | |
| Differentiating MDSCs | ARTA | NCT02403778 | Inhibits retinoic signaling to shift the differentiation of MDSC into mature myeloid cells, such as macrophages and dendritic cells | 147 |
| Blocking MDSCs trafficking | CXCR2 inhibitor (AZD5069, Reparixin, SX-682) | NCT03161431/NCT02499328/NCT02370238 | Inhibit CXCR2 mediated MDSCs trafficking | 94 |
| CCR2 inhibitor (BMS-813160, RS504393) | NCT04123379/NCT03767582/NCT03496662 | Improved the prognosis by blocking chemotaxis of M-MDSCs | 142 | |
| Inhibit MDSCs activity | Stat3 inhibitor (AZD9150) | NCT02499328 | A marked decrease in G-MDSC within the peripheral blood mononuclear cells | 158 |
| NF-κB inhibitor (BAY11-7082) | Pre-clinical | Inhibit the activated NF-kB signal induced by DAMPs-PRR interaction | 42 | |
| Targeting the ECM remodeling | LOX inhibitor (β-aminopropionitrile) | Pre-clinical | Reduce the surgery induced hypoxia related LOX, and ECM remodeling | 161 |
| Repair vascular leakage | IL-6 inhibitor (Tocilizumab) | NCT04370834) | Inhibit IL-6 mediated inflammatory response the repair the vascular leakage | 164 |
| C5 antibody (Ravulizumab) | NCT04369469 | Inhibit the C5a-C5R signal on vascular endothelial cells | 165 | |
| Restore the immunity after surgery | TGF-β inhibitor (LY3200882/LY2157299/EW-7197) | NCT04031872/NCT03143985/NCT02452008 | Reverse the MDSC secreted TGF-β mediated immunosuppression | 166 |
| PDE5 inhibitor (Sildenafil, Tadalafil) | NCT02544880 | Targeting MDSC expression and function of Arg-1 and iNOS | 167–169 | |
| ERAS | NCT02644603 | Pre-rehabilitation, nutrition, pain management to rapid restore immunity after surgery | 172 |