The Cathepsin Network: Multifaceted Regulators and Emerging Therapeutic Targets in Breast Cancer.

Abstract

Breast cancer metastasis remains the primary cause of mortality, driving the search for novel therapeutic vulnerabilities. The cathepsin family of lysosomal proteases has emerged as a pivotal signaling network that orchestrates tumor progression, therapy resistance, and organ-specific metastasis. This narrative review synthesizes current knowledge on key cathepsins (B, D, L, S, C, G, and V) in breast cancer, detailing their multifaceted roles in extracellular matrix remodeling, immune modulation, angiogenesis, and epigenetic regulation. We highlight their specialized functions: cathepsin B (CTSB) and cathepsin L (CTSL) as core executors of invasion; cathepsin S (CTSS), cathepsin C (CTSC), and cathepsin G (CTSG) as mediators of immune crosstalk and organotropic metastasis to brain, lung, and bone; and cathepsin D (CTSD)/cathepsin V (CTSV) as hormonally-linked regulators with nuclear roles. Critically, we evaluate the emerging preclinical strategies of cathepsins as diagnostic biomarkers and therapeutic targets, reviewing emerging strategies including small-molecule inhibitors, antibody-based therapies, activatable prodrugs, and imaging probes. Advancing the understanding of this context-dependent protease network and developing selective interventions hold significant promise for paving the way towards more effective and personalized treatment strategies.

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