2. Academic Validation
  3. ABCC10-mediated cGAMP efflux drives cancer cell radiotherapy resistance

ABCC10-mediated cGAMP efflux drives cancer cell radiotherapy resistance

  • Cell Death Differ. 2025 Aug 6. doi: 10.1038/s41418-025-01552-1.
Zhengyang Zhang # 1,  Jie Gao # 1 2,  Xiang Liao # 1,  Zining Zhang 1,  Xiongfeng Cao 1 2,  Yi Gong 1,  Wenlong Chen 1,  Lirong Zhang 1 2,  Hsiang-I Tsai 3 4,  Dongqing Wang 5 6,  Haitao Zhu 7 8
Affiliations

Affiliations

  • 1 Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China.
  • 2 Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, China.
  • 3 Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China. tsaihsiangi88@163.com.
  • 4 Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, China. tsaihsiangi88@163.com.
  • 5 Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China. wangdongqing71@163.com.
  • 6 Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, China. wangdongqing71@163.com.
  • 7 Institute of Medical Imaging and Artificial Intelligence, Jiangsu University, Zhenjiang, China. zhht25@163.com.
  • 8 Department of Medical Imaging, The Affiliated Hospital of Jiangsu University, Zhenjiang, China. zhht25@163.com.
  • # Contributed equally.
PMID: 40770563 DOI: 10.1038/s41418-025-01552-1
Abstract

Although radiotherapy (RT) is used in more than 50% of Cancer patients, the intrinsic radioresistance of Cancer cells, characterized by metabolic adaptation, significantly limits its clinical efficacy. However, the mechanisms underlying RT resistance (RTR) remain incompletely understood. In this study, we used high-throughput metabolic CRISPR library screening and identified ABCC10 as a novel molecular contributor to RTR. Functional assays, including vesicle transport, molecular docking, and an enzyme-linked immunosorbent assay, confirmed that the R545 site of ABCC10 binds to and effluxes 2'3'-cyclic GMP-AMP (cGAMP) in an ATP-dependent manner. Mechanistically, RNA transcriptomics, along with overexpression and silencing experiments, demonstrated that ABCC10-mediated export of cGAMP suppresses the STING-TBK1-IRF3 signaling pathway. This efflux reduces RT-induced intercellular accumulation of Reactive Oxygen Species and DNA damage. In vivo, a combination of RT and nilotinib, a potential ABCC10 inhibitor, synergistically inhibited tumor growth. In summary, we identified ABCC10 as a novel exporter of cGAMP in RTR. Our results highlight its potential role as a biomarker for predicting RT response and as a therapeutic target for overcoming RTR.

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