Table 1.

Potential small molecules that target DUBs to relieve immunosuppression and suppress tumorigenesis

DUB subfamily	DUB	Inhibitor/Compound	Cell-intrinsic DUB	Mechanism / Effect / Implication	Reference(s)
JAMMs	CSN5	Berberine	NSCLC	1. Selectively target Glu76 residue of CSN5 to decrease PD-L1 levels 2. Suppress MDSCs and Tregs activation but enhance effector T cell function and infiltration	[107]
		Curcumin	BC, NSCLC, Melanoma, CRC	1. Inhibit CSN5 activity to downregulate PD-L1 2. Synergize with anti-CTLA-4 mAb and promote effector T cell function	[55]
USPs	USP1	ML323	Macrophage	1. Inhibit USP1/ID1 signaling to upregulate CD8+ T-cell-recruiting factors (e.g., CCL4 and SerpinB2) 2. Increase CD8+ T cell infiltration and function and suppress colorectal liver metastasis 3. Improve CRC sensitivity to 5-FU and anti-CTLA-4 mAb	[19]
	USP5	EOAI34	CD8+ T-cell	1. Block USP5-mediated deubiquitination of PD-1 2. Combine with Trametinib (MEK inhibitor) to increase CD8+ T cell infiltration and exhibit growth inhibition in lung and colon cancer	[20]
	USP7	564	Treg	1. Reduce the recruitment and suppressive function of FoxP3+ Tregs 2. Improve the efficacy of antitumor vaccine and ICB in murine models bearing lung cancer or mesothelioma	[91]
		P5091	Macrophage	1. Activate p38 MAPK signaling to reprogram macrophage polarization towards M1 phenotype 2. Delay growth of lung cancer concomitant with increased M1 and CD8+ T cell infiltration	[52]
	USP8	9-Ethyloxyimino‐9 H‐indeno[1,2‐b]pyrazine‐2,3‐dicarbonitrile	BC	1. Decrease the stability of TβRII and circulating TβRII+ EVs to prevent CD8+ T cell exhaustion 2. Improve the efficacy of ICB but suppress metastasis	[118]
		DUBs-IN-2	Colon cancer and NSCLC	1. Increase PD-L1 levels through restoring TRAF6-mediated K63-linked ubiquitination 2. Promote MHC I expression and CD8+ T cell infiltration 3. Augment the tumor sensitivity to anti-PD-L1/PD-1 mAb	[22]
			PDAC	1. Decrease PD-L1 levels through directly targeting USP8-mediated deubiquitination of PD-L1 2. Synergize with anti-PD-L1 mAb to increase CD8+ T cell infiltration and function but suppress liver and lung metastasis	[21]
	USP14	IU1	Macrophage	1. Block USP14/SIRT-1/PGC-1α axis to metabolically reprogram TAMs 2. Inhibit EMT and tumor growth of GC	[45]

BC breast cancer, CCL4 C-C motif chemokine ligand 4, CRC, colorectal cancer, CSN5 COP9 signalosome 5, EMT epithelial–mesenchymal transition, EVs extracellular vesicles, GC gastric cancer, ICB, immune checkpoint blockade, JAMMs JAMM/MPN domain-associated metallopeptidases, MDSCs, myeloid-derived suppressor cells; NSCLC non-small cell lung cancer, PGC-1α peroxisome proliferator-activated receptor-γ coactivator-1α, SIRT-1 sirtuin-1, Tregs regulatory T cells, TβRII TGF-β receptor II, USPs ubiquitin-specific proteases