Protease inhibition: breaking the barriers of chemoresistance in cancer.

Chemoresistance remains a major barrier to effective cancer therapy, limiting durable responses across multiple malignancies. Proteases, including matrix metalloproteinases, cathepsins, ubiquitin-specific proteases, proteasome components, and mitochondrial proteases, contribute to chemoresistance through diverse mechanisms, including modulation of drug transport, extracellular matrix remodeling, epithelial-mesenchymal transition, apoptosis, and pro-survival signaling. Collectively, these processes promote a tumor microenvironment that facilitates therapeutic escape. This review critically synthesizes current mechanistic evidence together with available clinical studies on protease-mediated chemoresistance, emphasizing the gap between strong biological rationale and limited clinical success. Broad-spectrum protease inhibition has shown limited clinical success owing to insufficient isoform selectivity, compensatory signaling, inadequate biomarker-guided patient stratification, and limited pharmacodynamic validation. Emerging strategies focus on context-specific protease targeting, biomarker guided patient selection, rational combination therapy, and advanced drug delivery platforms, including protease-activated prodrugs and nanoparticle-based systems. Integration of proteomic profiling with functional validation may facilitate identification of protease dependencies and support more precise therapeutic interventions. Collectively, these advances suggest that protease inhibition may evolve from empirical enzyme blockade toward mechanism-driven approaches for overcoming chemoresistance, although further clinical validation remains necessary.