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  3. The low-dose CHK1 inhibitor prexasertib triggers VDAC1 dephosphorylation to activate mtDNA-STING signaling and synergize immunotherapy

The low-dose CHK1 inhibitor prexasertib triggers VDAC1 dephosphorylation to activate mtDNA-STING signaling and synergize immunotherapy

  • Cell Rep. 2025 May 27;44(5):115605. doi: 10.1016/j.celrep.2025.115605.
Yu Fu 1,  Xiaoyan Kang 1,  Wenting Li 2,  Zanhong Wang 3,  Wanwan Luo 1,  Bin Yang 1,  Yaoyuan Cui 1,  Funian Lu 1,  Tianyu Qin 1,  Xingyuan Hu 1,  Jingjing Yin 1,  Xi Li 1,  Junpeng Fan 1,  Beibei Wang 1,  Gang Chen 1,  Rourou Xiao 4,  Zhiqiang Han 5,  Ensong Guo 6,  Xu Qin 7
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang 832000, China.
  • 3 Department of Obstetrics and Gynecology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi 030032, China.
  • 4 Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China. Electronic address: xiaorourou@znhospital.cn.
  • 5 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Obstetrics and Gynecology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi 030032, China. Electronic address: hanzq2003@126.com.
  • 6 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: tjguoensong@tjh.tjmu.edu.cn.
  • 7 Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: xqin@hust.edu.cn.
PMID: 40249707 DOI: 10.1016/j.celrep.2025.115605
Abstract

Chk1 inhibitors exhibit dose-limiting toxicity despite potent tumor cytotoxicity in clinical trials. Here, we reveal that low-dose prexasertib induces mtDNA damage by impairing repair machinery, triggering cytosolic mtDNA release via VDAC1 to activate STING-mediated innate immunity. Mechanistically, prexasertib blocks Chk1 phosphorylation and competitively recruits NEK1 kinase, thereby activating the ATR/Chk1 signaling cascade. Consequently, it disrupts the phosphorylation of VDAC1 by NEK1 kinase at T107 and promotes the formation of VDAC1 oligomers, where mtDNA exits. In vivo, low-dose prexasertib exhibits immune-modulatory effects and synergizes safely with immune checkpoint blockade at subtherapeutic doses. Our findings establish reduced-dose Chk1 inhibition as a strategy to amplify immunotherapy efficacy while circumventing systemic toxicity, providing a translatable framework for optimizing therapeutic windows in clinical oncology.

Keywords

CHK1 inhibitor; CP: Cancer; DNA damage; STING; VDAC1; cell-cycle checkpoints; immunotherapy; mitochondrial membrane; mitochondrial-nuclear crosstalk.

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