Background <p>In recent years, extensive research has demonstrated that deubiquitination modifications of proteins play crucial roles in key biological processes such as tumor proliferation, apoptosis, metabolic reprogramming, and immune evasion, significantly influencing tumorigenesis, progression, and therapeutic response. The ubiquitin-specific protease (USP) family represents the largest and most structurally diverse group of deubiquitinating enzymes to date. Among them, USP5 has emerged as a central node regulating multiple signaling pathways due to its multi-domain architecture and extensive substrate spectrum. Research indicates that USP5 not only drives glycolipid metabolic reprogramming and epigenetic regulation by stabilizing key metabolic enzymes and transcription factors, but also plays critical roles in DNA damage repair, ferroptosis resistance, radiotherapy tolerance, and PD-1/PD-L1-mediated immune suppression. Furthermore, USP5 participates in the fine-tuning of multiple signaling pathways, promoting tumor stemness maintenance and malignant progression.</p> Main body <p>This review systematically outlines the multifunctional roles of USP5 in cancer, focusing on molecular mechanisms, metabolic reprogramming, and potential as a therapeutic target. It comprehensively explores the potential clinical applications of USP5 targeting in metabolic intervention, immune enhancement, and sensitization to radiotherapy and chemotherapy.</p> Conclusions <p>USP5 mediates metabolic reprogramming, tumor microenvironment remodeling, and the regulation of molecular pathways, playing a critical role in targeted therapy and radiosensitization, and demonstrating significant potential as a universal therapeutic target and tumor-specific biomarker.</p>