Ubiquitin-specific protease 7 (USP7): a key deubiquitinase governing tumor progression and therapeutic vulnerabilities

Ubiquitin-specific protease 7 (USP7), a core member of the deubiquitinating enzyme family, acts as a double-edged sword in tumorigenesis and progression by dynamically interacting with multiple substrate proteins via its TRAF domain. Beyond tumorigenesis, USP7 is indispensable for embryonic development and genome stability, and constitutive knockout in mice leads to early embryonic lethality, indicating its essential roles in maintaining physiological homeostasis.USP7 exerts context-dependent dual effects during tumorigenesis and progression. In most p53 wild-type malignancies under basal unstressed conditions, USP7 preferentially stabilizes MDM2 to accelerate p53 turnover, which facilitates tumor growth; yet under DNA damage stress, USP7 can directly deubiquitinate and activate p53 to trigger tumor-suppressive programs. Conversely, in p53 -mutant or p53 -null tumors lacking functional p53 checkpoint, USP7 predominantly sustains oncogenic phenotypes by stabilizing Myc, NF-κB, EZH2 and other oncoproteins, fueling proliferation, metabolic reprogramming, immune evasion and therapy resistance.USP7 regulates a wide spectrum of biological processes, including DNA damage repair, epigenetic modification, cell cycle progression and apoptosis. Although great advances have been made in the development of USP7-targeted small-molecule inhibitors, their clinical translation is hindered by on-target toxicity, insufficient selectivity, poor pharmacokinetics and context-dependent efficacy. Future research should focus on developing highly selective inhibitors, elucidating context-specific regulatory networks, exploring predictive biomarkers and optimizing combination regimens. As a druggable deubiquitinase target, USP7 facilitates the development of novel strategies to reverse clinical chemoresistance and implement personalized oncology.