Cancer management has traditionally depended on chemotherapy as the mainstay of treatment
however, recent advancements in targeted therapies and immunotherapies have offered new options. Ubiquitin-specific proteases (USPs) have emerged as promising therapeutic targets in cancer treatment due to their crucial roles in regulating protein homeostasis and various essential cellular processes. This review covers the following: (1) the structural and functional characteristics of USPs, highlighting their involvement in key cancer-related pathways, and (2) the discovery, chemical structures, mechanisms of action, and potential clinical implications of USP inhibitors in cancer therapy. Particular attention is given to the role of USP inhibitors in enhancing cancer immunotherapy, e.g., modulation of the tumor microenvironment, effect on regulatory T cell function, and influence on immune checkpoint pathways. Furthermore, this review summarizes the current progress and challenges of clinical trials involving USP inhibitors as cancer therapy. We also discuss the complexities of achieving target selectivity, the ongoing efforts to develop more specific and potent USP inhibitors, and the potential of USP inhibitors to overcome drug resistance and synergize with existing cancer treatments. We finally provide a perspective on future directions in targeting USPs, including the potential for personalized medicine based on specific gene mutations, underscoring their significant potential for enhancing cancer treatment. By elucidating their mechanisms of action, clinical progress, and potential future applications, we hope that this review could serve as a useful resource for both basic scientists and clinicians in the field of cancer therapeutics.