Selective BCL-2 inhibitor triggers STING-dependent antitumor immunity via inducing mtDNA release

作者：Wenxin Zhang, Xiaohui Pan, Longsheng Wang, Wen Li, Xiaoyang Dai, Mingming Zheng, Hongjie Guo, Xi Chen, Yanjun Xu, Honghai Wu, Qiaojun He, Bo Yang, Ling Ding · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-010889 · 被引用次数：8 · 研究领域：interferon and immune responses、Immune Response and Inflammation、Cytokine Signaling Pathways and Interactions

BACKGROUND: The stimulator of interferon genes (STING) signaling pathway has been demonstrated to propagate the cancer-immunity cycle and remodel the tumor microenvironment and has emerged as an appealing target for cancer immunotherapy. Interest in STING agonist development has increased, and the candidates hold significant promise; however, most are still in the early stages of human clinical trials. We found that ABT-199 activated the STING pathway to enhance the immunotherapeutic effect, and provided a ready-to-use small molecule drug for STING signaling activation. METHODS: Phosphorylation of STING, TBK1, and IRF3, as well as activation of the interferon-I (IFN-I) signaling pathway, were detected following ABT-199 treatment in various colorectal cancer cells. C57BL/6J and BALB/c mice with subcutaneous tumors were employed to evaluate the in vivo therapeutic effects of the ABT-199 and anti-PD-L1 combination. Flow cytometry and ELISA were employed to analyze the level and activity of tumor-infiltrating T lymphocytes. Immunofluorescence and quantitative real-time PCR were conducted to assess the source and accumulation of double stranded DNA (dsDNA) in the cytoplasm. Chemical cross-linking assay, co-immunoprecipitation, and CRISPR/Cas9-mediated knockout were performed to investigate the molecular mechanism underlying ABT-199-induced voltage-dependent anion channel protein 1 (VDAC1) oligomerization and mitochondrial DNA (mtDNA) release. RESULTS: ABT-199 significantly activat...