FDX1
Depletion Activates
CD8
+
T Cell Antitumor Immunity by Promoting
DMBT1
Secretion
Jieqiong Wu, Zaixi Lian, Mingzhou Li, Xingtu Qin, Xiaoyu Lei, Lihua Yang, Lin Bing, Qiuyue Li, Lingyan Zhou, Zhiyang Ma, Xuemei Xu, Jinghao Huang, Zilong Chen, Lijie Chen, Lingjie Zhang, Zhiyuan Xiao, Xiangyu Jian, Xiaoqin Zhang, Yanqing Ding, Yaping Ye, Li Liang, Hongli Jiao, Shuyang Wang ABSTRACT
Cuproptosis, a copper‐dependent form of regulated cell death, has been documented in colorectal cancer (CRC), yet its impact on the tumor immune microenvironment remains incompletely understood. Here, we demonstrate that elesclomol‐induced cuproptosis potently activates innate and adaptive antitumor immunity, markedly enhancing CD8 + T cell cytotoxicity while attenuating exhaustion. Mechanistically, FDX1, which correlates inversely with CD8 + T cell infiltration and predicts poor prognosis, functions as a core regulator of CD8 + T cell functionality during cuproptosis. FDX1 promotes CRC proliferation and metastasis while suppressing CD8 + T cell cytokine production. We further show that FDX1 binds DICER1 to reduce DMBT1 mRNA stability, with FDX1 and DMBT1 expression exhibiting significant negative correlation in CRC tissues. Our findings establish the FDX1–DICER1–DMBT1 axis as a critical regulator of CRC progression and immune evasion, suggesting that therapeutic targeting of this pathway could enhance antitumor immunity and overcome resistance to existing immunotherapies.