DPP7 Promotes Colorectal Cancer Progression Through GPX4-Dependent Suppression of Disulfidptosis and Immune Evasion

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, highlighting the need to identify novel mechanisms driving tumour progression. In this study, we demonstrate that dipeptidyl peptidase 7 (DPP7) high expression correlates with poor prognosis in CRC patients. Functional analyses revealed that DPP7 promotes CRC cell proliferation and inhibits apoptosis, while its depletion enhances natural killer (NK) cell-mediated cytotoxicity against tumour cells. Mechanistically, we identified a previously unknown role of DPP7 in suppressing disulfidptosis, a novel form of regulated cell death characterised by excessive formation of intracellular disulfide bonds. DPP7 overexpression protected CRC cells from glucose deprivation-induced disulfidptosis, as evidenced by reduced disulfide bond formation in cytoskeletal proteins including drebrin, FLNA and FLNB. Furthermore, we discovered that DPP7 physically interacts with glutathione peroxidase 4 (GPX4), a key regulator of cellular redox homeostasis, and stabilises GPX4 protein without affecting its mRNA expression. GPX4 restoration in DPP7-depletion cells reversed the enhanced sensitivity to both disulfidptosis and NK cell-mediated killing, while GPX4 depletion abolished the protective effect of DPP7 overexpression. Our findings unveil a novel DPP7-GPX4 axis in regulating disulfidptosis and immune evasion in colorectal cancer, providing potential therapeutic targets for CRC treatment. Targeting this pathway may simultaneously inhibit tumour cell survival mechanisms and enhance immune-mediated tumour elimination.