双特异性磷酸酶4（DUSP4）在微卫星高度不稳定（MSI）结直肠癌中抑制铁死亡及促进CD8 T细胞细胞毒性方面的新作用

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

作者信息

Zhang Dongsheng, Yang Sheng, Xu Hengjie, Chen Zhihao, Wang Xiaowei, Sun Yueming

机构信息

Department of General Surgery, Colorectal Institute of Nanjing Medical University, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.

出版信息

Br J Cancer. 2025 Aug 22. doi: 10.1038/s41416-025-03119-w.

DOI:10.1038/s41416-025-03119-w

PMID:40847010

Abstract

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.

摘要

背景

微卫星不稳定（MSI）结直肠癌（CRC）具有与微卫星稳定CRC不同的特征。虽然铁死亡可能在MSI CRC的发生发展中起作用，但其机制仍不清楚。

方法

通过检测脂质过氧化、丙二醛、4-羟基壬烯醛和细胞内Fe2+等来评估铁死亡。进行磷酸化蛋白质组分析、细胞因子阵列分析和流式细胞术以探讨CD8 T细胞浸润的调节机制。

结果

双特异性磷酸酶4（DUSP4）通过减少脂质过氧化和抑制细胞内Fe2+积累来抑制MSI CRC细胞中的铁死亡。机制研究表明，DUSP4下调转铁蛋白受体（TFRC）的表达，而TFRC的表达受c-MYC转录调控。此外，在CRC组织中观察到CD8 T细胞浸润与癌细胞中DUSP4的表达呈正相关。机制上，DUSP4使细胞周期蛋白依赖性激酶7（CDK7）去磷酸化并促进C-X-C基序趋化因子配体16（CXCL16）的表达，从而导致CD8 T细胞浸润增加。重要的是，CDK7抑制剂与抗程序性细胞死亡蛋白1疗法的联合应用在MSI CRC中显示出协同治疗效果。