Cathepsin L in cancer: Context-dependent functions, microenvironmental regulation and translational opportunities

Abstract

Background

Cathepsin L (CTSL), a lysosomal cysteine endopeptidase, is implicated in multiple facets of tumour biology beyond its canonical role in intracellular protein turnover.

Objective

This review provides a comprehensive synthesis of the current evidence regarding CTSL in cancer, evaluating its biochemical constraints, substrate selectivity within the cysteine cathepsin family, and context-dependent functions across diverse malignancies.

Key findings

Mechanistically, across solid and haematological malignancies, such as breast and gastrointestinal cancers as well as paediatric acute myeloid leukaemia, CTSL promotes progression and therapy resistance through diverse processes, including extracellular matrix degradation, epithelial–mesenchymal transition, angiogenesis, and cell proliferation. These oncogenic functions are strongly context- and lineage-dependent rather than operating through a universal mechanism. Conversely, in stratified squamous epithelia, including the epidermis and cutaneous squamous cell carcinoma models, CTSL can exert tumour-suppressive effects by promoting EGFR degradation and limiting aberrant mitogenic signalling. In the tumour microenvironment, CTSL influences tumour immune evasion, myeloid-cell polarisation, and lymphocyte homeostasis. Translational studies have investigated CTSL in relation to prognosis and treatment response. In addition, its proteolytic activity has been exploited in engineered applications, including protease-cleavable antibody-drug conjugate linkers and activity-based diagnostic probes.

Conclusions

Rather than acting as a universal driver, CTSL is a context-dependent modulator in cancer biology. Although no CTSL inhibitor has yet received clinical approval due to unfavourable ADME properties, off-target toxicity, and compensatory mechanisms, the development of selective extracellular-targeting strategies and companion diagnostics highlights its continuing promise as a therapeutic and diagnostic target in oncology.