Regulatory roles of five key USP family deubiquitinases in cancer: from mechanisms to targeted therapy advances.

Ubiquitination is a crucial post-translational modification of proteins in eukaryotic cells. Deubiquitinating enzymes (DUBs) remove ubiquitin molecules from substrate proteins, thereby reversing ubiquitination and maintaining intracellular ubiquitin homeostasis. Dysregulation or dysfunction of DUBs is closely associated with various diseases. Among them, the ubiquitin-specific protease (USP) family, the largest subfamily of DUBs, plays a key regulatory role in tumor initiation and progression. This article systematically reviews the research progress on five representative USP family members closely linked to tumors, including USP7, USP22, USP10, USP35, and USP4, with a focus on their functional mechanisms in regulating major tumor-related signaling molecules and pathways, including p53, PTEN, c-Myc, and PD-L1. It also highlights their dual regulatory roles in tumor proliferation, resistance to apoptosis, metastasis, and immune evasion. Furthermore, this review summarizes the structural basis of USP catalysis and selectivity, the determinants of context-dependent USP functions, and the emerging roles of DUBs in tumor microenvironment remodeling and therapy resistance. We also discuss the latest advances in the development of selective inhibitors and new therapeutic modalities targeting these USPs, including PROTAC-mediated degradation, DUBTAC-mediated tumor suppressor stabilization, and molecular glue strategies. Although targeting DUBs for cancer therapy faces challenges such as substrate diversity, context-dependent functions, and functional redundancy within the family, it remains a promising strategy for tumor treatment. This review provides a theoretical foundation and research directions for further understanding the roles and mechanisms of the USP family in cancer and for developing targeted DUB-based anti-tumor therapies.