The low-dose CHK1 inhibitor prexasertib triggers VDAC1 dephosphorylation to activate mtDNA-STING signaling and synergize immunotherapy
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.
Authors
- Rourou Xiao
- Ensong Guo (ORCID: https://orcid.org/0000-0002-7388-4324)
- Tianyu Qin (ORCID: https://orcid.org/0000-0002-5897-871X)
- Xingyuan Hu (ORCID: https://orcid.org/0000-0001-5225-377X)
- Jingjing Yin (ORCID: https://orcid.org/0000-0003-2325-2713)
- Zanhong Wang (ORCID: https://orcid.org/0000-0002-1339-4411)
- W. Luo (ORCID: https://orcid.org/0000-0002-8832-0193)
- Yu Fu (ORCID: https://orcid.org/0000-0001-9849-7841)
- Xiaoyan Kang (ORCID: https://orcid.org/0009-0001-5947-0205)
- Yaoyuan Cui
- Zhiqiang Han (ORCID: https://orcid.org/0000-0002-2898-2195)
- Beibei Wang (ORCID: https://orcid.org/0000-0003-2362-2905)
- Gang Chen (ORCID: https://orcid.org/0000-0002-5183-9303)
- Bin Yang (ORCID: https://orcid.org/0000-0001-5534-9187)
- Wenting Li (ORCID: https://orcid.org/0000-0002-1074-0956)
- Qin Xu (ORCID: https://orcid.org/0000-0002-2146-7342)
- Funian Lu (ORCID: https://orcid.org/0000-0003-4864-4967)
- Zhiheng Li (ORCID: https://orcid.org/0000-0002-2977-2624)
- Junpeng Fan (ORCID: https://orcid.org/0000-0002-9413-408X)
Institutions
- Wuhan University (CN)
- Zhongnan Hospital of Wuhan University (CN)
- First Affiliated Hospital of Shihezi University Medical College (CN)
- Shanxi Academy of Medical Sciences (CN)
- Tongji Hospital (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1016/j.celrep.2025.115605
- Citations
- 5
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 3.99