Cathepsin E drives colorectal cancer progression and immune evasion via ZNF326 ADP-ribosylation and TGF-β/SMAD activation.

[BACKGROUND] Colorectal cancer (CRC) is a leading malignant tumor worldwide with rising morbidity and mortality. Cathepsin E (CTSE), a member of the cysteinyl asparaginase family, is implicated in immune responses, antigen processing, and cellular signaling.

[METHODS] The biological functions of CTSE in CRC were assessed through in vitro and in vivo experiments evaluating proliferation, invasion, and metastasis. Mechanistic studies utilized knockdown approaches, pathway inhibition, and analysis of post-translational modifications to investigate CTSE-mediated ADP-ribosylation. The impact of CTSE on tumor immunity was examined by analyzing PD-L1/PD-1 interactions and CD8 T cell-mediated cytotoxicity.

[RESULTS] CTSE promoted CRC proliferation, invasion, metastasis, and immune escape. Mechanistically, CTSE stabilized ZNF326 by promoting its ADP-ribosylation at glutamate 338, thereby activating TGF-β/SMAD pathway. The tumor-promoting effect was abolished by ZNF326 knockdown or TGF-β/SMAD pathway inhibition. Furthermore, CTSE enhanced PD-L1/PD-1 interactions and reduced secretion of anti-tumor factors, thereby impairing CD8 T cell recognition and killing of tumor cells.

[CONCLUSIONS] CTSE drives CRC progression by stabilizing ZNF326 via ADP-ribosylation and activating TGF-β/SMAD pathway, while facilitating tumor immune evasion. CTSE represents a promising therapeutic target for CRC, and its combination with PD-1/PD-L1 inhibitors may synergistically enhance anti-tumor efficacy.