USP22 in human cancers: mechanistic insights and inhibitor development.

Ubiquitination plays a crucial role in cancer initiation and development by regulating protein stability and functions. Deubiquitinases (DUBs) are key enzymes in this process, primarily responsible for removing ubiquitin chains from substrate proteins, thereby preventing protein degradation and regulating diverse cellular signaling pathways. Ubiquitin-specific peptidase 22 (USP22), a member of the ubiquitin-specific protease (USP) subfamily of DUBs, critically deubiquitinates histones and various oncogenic proteins such as cellular myelocytomatosis viral oncogene homolog (c-Myc), forkhead box protein 3 (FOXP3), and hypoxia-inducible factor 1-alpha (HIF-1α). USP22 is frequently dysregulated in cancers and associated with tumor progression, cancer stemness, invasion, therapy resistance, and immune evasion. Thus, USP22 has emerged as a promising novel therapeutic target in oncology. Recent studies have demonstrated that inhibition of USP22 can effectively suppress tumor growth, enhance antitumor immune responses, and overcome drug resistance in preclinical models. Nevertheless, the clinical translation of USP22 inhibitors continues to encounter challenges. In this review, we summarize the role of USP22 in cancer and discuss recent progress in developing novel USP22 inhibitors as antitumor agents.