Legumain Function in Cancer Biology

Legumain, also known as asparaginyl endopeptidase (AEP), is a cysteine protease predominantly localised to the endolysosomal compartment. It exhibits strict specificity for asparagine residues and participates in antigen processing, extracellular matrix remodelling and regulation of autophagy. In many solid tumours, legumain is overexpressed not only within malignant cells but also in stromal cells such as tumour‐associated macrophages. Its aberrant activity promotes invasion and metastasis through activation of matrix metalloproteinases and modulation of integrin signalling. Beyond canonical proteolysis, legumain can translocate to non‐lysosomal compartments, where pH‐dependent shifts endow it with novel ligase or carboxypeptidase functions. These multifaceted roles extend to shaping the immune microenvironment, influencing genomic stability and driving resistance to chemotherapy and radiotherapy. As a result, legumain has emerged as both a prognostic biomarker and a promising therapeutic target in cancer biology.

Research from Nature Portfolio

Recent studies have demonstrated gene editing of legumain with CRISPR/Cas9 delivered by lipid nanoparticles. This approach effectively disrupts legumain expression, impairs lysosomal and autophagic functions, reduces colony formation, migration and invasion in vitro, and attenuates lung metastasis in vivo. The work highlights the feasibility of lipid‐based co‐delivery of Cas9 mRNA and guide RNAs as a precision strategy to modulate endolysosomal protease activity and suggests a potential therapeutic route to limit tumour dissemination by targeting legumain at the genomic level.

Legumain Function in Cancer Biology publication trend

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

Technical terms

Endolysosomal protease: An enzyme localised in endosomes and lysosomes that catalyses peptide bond hydrolysis under acidic conditions.

Autophagy: A regulated process wherein cells degrade and recycle cytoplasmic constituents via lysosomal pathways.

M2 polarisation: A macrophage activation state characterised by anti‐inflammatory and tissue‐remodelling functions that can support tumour growth.

Integrin αvβ3: A cell surface receptor that mediates cell–matrix adhesion and intracellular signalling relevant to metastasis and angiogenesis.

CRISPR/Cas9 gene editing: A genome engineering technology that uses a guide RNA and Cas9 nuclease to introduce targeted DNA modifications.

References

1. Structure and function of legumain in health and disease. Biochimie (2015).
2. The Mechanism of Asparagine Endopeptidase in the Progression of Malignant Tumors: A Review. Cells (2021).
3. Nuclear Legumain Activity in Colorectal Cancer. PLOS ONE (2013).
4. Distinct Roles of Catalytic Cysteine and Histidine in the Protease and Ligase Mechanisms of Human Legumain As Revealed by DFT-Based QM/MM Simulations. ACS Catalysis (2017).
5. Radiotherapy resistance driven by Asparagine endopeptidase through ATR pathway modulation in breast cancer. Journal of Experimental & Clinical Cancer Research (2025).
6. Expression of Legumain Correlates with Prognosis and Metastasis in Gastric Carcinoma. PLOS ONE (2013).
7. Co-delivery of Cas9 mRNA and guide RNAs for editing of LGMN gene represses breast cancer cell metastasis. Scientific Reports (2024).
8. Cancer Cell Secreted Legumain Promotes Gastric Cancer Resistance to Anti-PD-1 Immunotherapy by Enhancing Macrophage M2 Polarization. Pharmaceuticals (2024).