{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:43:02Z","timestamp":1792597382613,"version":"4.5.0"},"reference-count":45,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"unspecified","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273949"],"award-info":[{"award-number":["82273949"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82330114"],"award-info":[{"award-number":["82330114"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LD25H300002"],"award-info":[{"award-number":["LD25H300002"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,4,10]]},"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>ABT-199 significantly activated the STING signaling pathway in various colorectal cancer cells, which was evidenced by increased phosphorylation of TBK1 and IRF3, and upregulation of C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 10 (CXCL10), and interferon beta transcription. By promoting chemokine expression and cytotoxic T-cell infiltration, ABT-199 promoted antitumor immunity and synergized with anti-PD-L1 therapy to improve antitumor efficacy. ABT-199 induced mtDNA accumulation in the cytoplasm and triggered STING signaling via the canonical pathway. cGAS or STING-KO models significantly abolished both STING signaling activation and the antitumor efficacy of ABT-199. Mechanically, ABT-199 promoted VDAC1 oligomerization by disturbing the binding between BCL-2 and VDAC1, thereby facilitating mtDNA release into the cytoplasm. ABT-199-triggered STING signaling was attenuated when VADC1 was knocked out. Consistently, the antitumor effect of ABT-199 in vivo was abolished in the absence of VDAC1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results identify a ready-to-use small molecule compound for STING activation, reveal the underlying molecular mechanism through which ABT-199 activates the STING signaling pathway, and provide a theoretical basis for the use of ABT-199 in cancer immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-010889","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T21:55:11Z","timestamp":1745963711000},"page":"e010889","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Selective BCL-2 inhibitor triggers STING-dependent antitumor immunity via inducing mtDNA 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