Cysteine Protease Functionality in Cancer Biology

Cysteine proteases constitute a class of thiol-dependent enzymes that orchestrate protein turnover and signal transduction in both physiological and pathological contexts. In cancer biology, members of the cathepsin family—particularly cathepsins B, L, S and K—drive tumour progression by degrading extracellular matrix components, facilitating invasion and metastasis, and reshaping the tumour microenvironment. Beyond bulk proteolysis, these enzymes activate growth factors, modulate cytokine networks and influence immune cell recruitment. Zymogen activation within acidic endolysosomal compartments and subsequent secretion into the extracellular milieu enable cysteine proteases to act at multiple sites, from lysosomes to the cell surface and extracellular matrix. Dysregulated expression of these enzymes correlates with poor prognosis in various solid tumours, making them attractive biomarkers and therapeutic targets. Efforts to develop selective inhibitors—ranging from small-molecule warheads to antibody-based approaches—seek to interrupt protease-mediated epithelial–mesenchymal transition, angiogenesis and the immunosuppressive niche, while preserving essential homeostatic functions in normal tissues.

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Cysteine Protease Functionality in Cancer Biology publication trend

The graph below shows the total number of articles in cysteine protease functionality in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Cysteine protease: A thiol-dependent enzyme that uses an active-site cysteine to cleave peptide bonds.

Tumour microenvironment (TME): The cellular and non-cellular milieu surrounding tumour cells, including immune cells, stroma and extracellular matrix.

Tumour-associated macrophages (TAMs): Macrophages within the TME that acquire a spectrum of phenotypes from pro-inflammatory (M1) to immunosuppressive (M2).

Activity-based probe (ABP): A chemical tool that binds covalently to the active form of an enzyme, enabling detection and profiling of protease activity.

Epithelial–mesenchymal transition (EMT): A cellular programme in which epithelial cells lose polarity and adhesion, acquiring migratory and invasive properties.

Zymogen: An inactive precursor of a protease that requires proteolytic cleavage or conformational change for activation.

References

1. Cathepsin D promotes polarization of tumor-associated macrophages and metastasis through TGFBI-CCL20 signaling. Experimental & Molecular Medicine (2024).
2. Development and Application of Reversible and Irreversible Covalent Probes for Human and Mouse Cathepsin‐K Activity Detection, Revealing Nuclear Activity. Advanced Science (2024).
3. Impact of the Warhead of Dipeptidyl Keto Michael Acceptors on the Inhibition Mechanism of Cysteine Protease Cathepsin L. ACS Catalysis (2023).