Abstract
BACKGROUND AND OBJECTIVE: With increasing incidence and clinical heterogeneity, prostate cancer (PCa) treatment remains challenging. Cathepsins (CTSs) contribute to PCa progression by remodeling the tumor microenvironment (TME). Their elevated expression is linked to poor outcomes. This review outlines the roles of CTSs in PCa pathogenesis, metastasis, and therapy resistance, and evaluates their biomarker and therapeutic potential. METHODS: A narrative review of the PubMed, Embase, and Web of Science databases was conducted from 2000 to 2025. Keywords such as "prostate", "cathepsin", "cancer", "angiogenesis", "immune", "EMT", and "therapy" were used to find relevant studies. The review includes randomized controlled trials, meta-analyses, animal studies, and reviews. The final search was conducted on October 19, 2025. KEY CONTENT AND FINDINGS: The role of CTSs in PCa: (I) cell survival. CTSs are crucial for PCa cell survival, influencing proliferation, migration, and invasion. Knockdown of specific CTSs significantly reduces these behaviors. CTSs also regulate cell death pathways such as apoptosis and autophagy, contributing to tumor progression. (II) TME regulation. CTSs degrade extracellular matrix (ECM) components, enhancing tumor invasion and metastasis. They also promote angiogenesis by upregulating VEGF and MMPs, and influence immune evasion, contributing to therapy resistance. (III) Bone metastasis: bone is a common site of PCa metastasis. CTSs contribute to the epithelial-mesenchymal transition (EMT), a process through which tumor cells adopt a mesenchymal phenotype, thereby enhancing metastatic potential and therapy resistance. Specifically, CTSs, including cathepsin K (CTSK) and cathepsin Z (CTSZ), play a key role in the bone microenvironment, facilitating tumor colonization and osteoclast-mediated bone resorption. (IV) Therapy resistance: CTSs contribute to resistance against chemotherapy, immunotherapy, and radiotherapy by modulating EMT, angiogenesis, and immune escape mechanisms. (V) Clinical application of CTSs: CTSs are potential biomarkers for early PCa detection and monitoring metastasis. CTS inhibitors have shown promise in preclinical models for inhibiting tumor invasion, angiogenesis, and bone resorption, suggesting therapeutic potential. CONCLUSIONS: CTSs are critical players in PCa progression and therapy resistance. Targeting CTSs may improve therapeutic outcomes, though further research is needed to better understand their mechanisms and clinical applicability.