Table 1.

New therapeutic strategies targeting immune checkpoints.

Drug candidate	Function	Mechanism	Reference
2F-Fuc	Downregulate PD-1	Core fucosylation is required for PD-1 surface expression. 2F-Fuc inhibits fucosylation to reduce PD-1 surface levels on activated T cells.	18
IL-2		IL-2 induces Fbxo38 expression through STAT5, which in turn mediates PD-1 ubiquitination and degradation.	22
Gefitinib	Downregulate PD-L1	GSK3β interacts with PD-L1 and induces degradation of PD-L1 by β-TrCP. EGF signaling inactivates GSK3β to stabalize PD-L1 in basal-like breast cancer. Gefitinib inhibits EGF signaling to destabilize PD-L1.	34
Metformin		Metformin activates AMPK to phosphorylate PD-L1 at S195, which leads to abnormal PD-L1 glycosylation and ERAD-mediated PD-L1 degradation.	27
Etoposide		EMT induces expression of N-glycosyltransferase STT3, which is required for PD-L1 glycosylation and stabilization. Etoposide inhibits EMT/β-catenin/STT3/PDL1 axis to downregulate PD-L1.	26
Peptide (PD-LYSO)		PD-LYSO consists of PD-L1-binding sequence and lysosome-sorting signal of HIP1R to target PD-L1 for lysosomal degradation.	32
Curcumin		CSN5 stabilizes PD-L1 via deubiquitination. Curcumin inhibits enzyme activity of CSN5 to destabilize PD-L1.	35
2-bromopalmitate		Inhibition of PD-L1 palmitoylation abolishes its suppression of PD-L1 mono-ubiquitination and degradation.	36
Palbociclib	Upregulate PD-L1	CDK4/6 inhibitor palbociclib inhibits Cyclin D1-CDK4-mediated phosphorylation and stabilization of SPOP, an E3 ligase for PD-L1, causing upregulation of PD-L1 in cancer cells.	33
pH-sensitive anti-CTLA-4 antibody	Abrogate irAE	pH-sensitive anti-CTLA-4 antibody prevents antibody-triggered lysosomal degradation of CTLA-4 and attenuates irAE.	130