Emerging roles of USP7 in tumor immune evasion, metabolic reprogramming, and therapeutic resistance

Ubiquitin-specific protease 7 (USP7) is a multifunctional deubiquitinase that has emerged as an important regulator of cancer progression, with growing evidence linking it to tumor immune evasion, metabolic adaptation, and therapeutic resistance. USP7 promotes immune suppression by stabilizing checkpoint molecules such as PD-L1, modulating FGL1/LAG-3 signaling, reshaping tumor-associated macrophage polarization, and reinforcing T-cell dysfunction. Simultaneously, USP7 regulates metabolic adaptation by maintaining lipid homeostasis, redox balance, ferroptotic resistance, and nutrient stress responses, thereby supporting tumor survival under adverse conditions. These intertwined immune and metabolic functions collectively contribute to resistance against immune checkpoint blockade, targeted therapy, and other anticancer interventions. Pharmacological inhibition of USP7 has shown promise in reprogramming the tumor microenvironment, exposing metabolic vulnerabilities, and sensitizing tumors to combination therapies. This review summarizes current insights into USP7 structure and substrate networks, highlights its multifaceted roles in tumor immunity and metabolism, and discusses the therapeutic potential and translational challenges of targeting USP7 in cancer.