Table 1.

Role of Ubiquitination and Deubiquitination in Regulation of PD-1/PD-L1 for Cancer Development and Immunotherapy

Regulators	PTM	Mechanism	Regulation of PD-1/PD-L1	Types of Cancer	Function in Immune or Tumor Cells	Related Molecules	References
β-TrCP	ubiquitination	regulates ubiquitination and degradation of PD-L1	inhibits PD-L1 level	breast cancer	modulates immune escape	GSK3β, mTORC1/p70S6K	40
CSN5	ubiquitination	suppresses the ubiquitination and degradation of PD-L1	increases PD-L1 level	breast cancer	results in immune system evasion	TNF-α, NF-κB p65	20
	deubiquitination	promotes deubiquitination and stabilization of PD-L1	upregulates PD-L1 expression	colorectal cancer	promotes cancer progression and migration	IκBa, Snail, CCL5, p65/STAT3	20,55
SPOP	ubiquitination	enhances ubiquitination-mediated degradation of PD-L1	decreases PD-L1 level	prostate cancer	increases TILs in cancer site, inhibits tumor extinction	Cullin 3, cyclin D-CDK4	63
STUB1	ubiquitination	induces ubiquitination and destabilization of PD-L1	downregulates level of PD-L1	–	negatively modulates immune activity	–	21
FBXO38	ubiquitination	enhances ubiquitination-mediated proteasomal degradation of PD-1	decreases PD-1 expression	melanoma	enhances T cell antitumor activity and tumor regression	–	22
DCUN1D	ubiquitination	unknown	increases PD-L1 level	lung cancer	promotes the development of cancer	FAK pathway	81
Cbl-b/c-Cbl	ubiquitination	accelerates ubiquitination of STAT5a	decreases PD-L1 level	melanoma, gastric cancer, NSCLC	promotes immunosuppression	STAT5a, AKT, and ERK signaling pathways	31,94,95
c-Cbl	ubiquitination	enhances ubiquitination-mediated degradation of PD-1	suppresses PD-1 activity	CRC	inhibits cancer development and immune infiltrates	–	96
HRD1	ubiquitination	modulates ubiquitination of PD-L1	downregulates PD-L1 level	–	improves the efficacy of immunosuppressive therapy	ERAD	105
USP22	deubiquitination	promotes deubiquitination and stability of PD-L1	increases expression of PD-L1	H22 tumor, lung cancer	promotes tumor growth and inhibits immune elimination	CSN5	107,139
USP9X	deubiquitination	modulates deubiquitination-induced stabilization of PD-L1	increases PD-L1, inhibits PD-1 level	OSCC	suppresses cancer cell proliferation	–	23,115