ABCC10-mediated cGAMP efflux drives cancer cell radiotherapy resistance

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.