The novel role of DUSP4 in suppressing ferroptosis and promoting cytotoxicity of CD8+ T cells in MSI colorectal cancer.

Background: Microsatellite instable (MSI) colorectal cancer (CRC) has distinct features that distinguish it from microsatellite stable CRC. While ferroptosis may play a role in the development of MSI CRC, its mechanisms remain unclear.

Methods: Ferroptosis was assessed via the detection of lipid peroxidation, malondialdehyde, 4-hydroxy-2-nonenal, and intracellular Fe2⁺, etc. Phosphoproteomic analysis, cytokine array, and flow cytometry were performed to explore the regulation of CD8⁺ T cell infiltration.

Results: Dual specificity phosphatase 4 (DUSP4) suppressed ferroptosis in MSI CRC cells by reducing lipid peroxidation and inhibiting intracellular Fe2⁺ accumulation. Mechanistic studies showed that DUSP4 downregulated the expression of transferrin receptor (TFRC), which was transcriptionally regulated by c-MYC. In addition, a positive correlation was observed between the infiltration of CD8⁺ T cells in CRC tissues and the expression of DUSP4 in cancer cells. Mechanistically, DUSP4 dephosphorylated cyclin-dependent kinase 7 (CDK7) and promoted C-X-C Motif chemokine ligand 16 (CXCL16) expression, resulting in an increased infiltration of CD8⁺ T cells. Importantly, the combination of a CDK7 inhibitor and anti-programmed cell death protein-1 therapy demonstrated a synergistic therapeutic effect in MSI CRC.

Conclusion: DUSP4 acts as a negative regulator of ferroptosis and a positive regulator of CD8⁺ T cell infiltration in MSI CRC.