2. Academic Validation
  3. Oxoisoaporphine Alkaloid Piano-Stool Arene Ruthenium(II) Derivative: A cGAS-STING-Mediated Chemoimmunotherapy Inducer that Acts as a Dual Catalytic Inhibitor of Topoisomerase I/II

Oxoisoaporphine Alkaloid Piano-Stool Arene Ruthenium(II) Derivative: A cGAS-STING-Mediated Chemoimmunotherapy Inducer that Acts as a Dual Catalytic Inhibitor of Topoisomerase I/II

  • J Am Chem Soc. 2026 Apr 8;148(13):14514-14525. doi: 10.1021/jacs.6c01872.
Liang-Mei Yang 1,  Yuan Lu 1 2,  Matthew S Levine 3,  Xue Wang 1,  Ya-Qian Shi 1,  Feng-Yang Wang 4,  Wei Zhang 1,  Jonathan L Sessler 3,  Hong Liang 1,  Ke-Bin Huang 1
Affiliations

Affiliations

  • 1 Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
  • 2 Guangxi College Key Laboratory of Innovation Research on Medical and Engineering Integration & Liuzhou Key Laboratory of Guizhong Characteristic Medicinal Resources Development, School of Medicine, Guangxi University of Science and Technology, Liuzhou 545005, China.
  • 3 Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712-1224, United States.
  • 4 Guangxi Colleges and Universities Key Laboratory of Pharmaceutical Biotechnology and Translational Medicine, School of Laboratory Medicine and Biotechnology, Guilin Medical University, Guilin 541004, China.
PMID: 41910318 DOI: 10.1021/jacs.6c01872
Abstract

Chemoimmunotherapy, particularly strategies that induce immunogenic cell death, has emerged as a promising approach to improved Cancer treatment. Nonetheless, only a limited number of drugs can successfully stimulate an antitumor immune response in vivo. Recent studies have highlighted the potential of metal-based Anticancer agents in chemoimmunotherapy. Herein, we report a novel piano-stool arene ruthenium(II) complex, Ru-4, which acts as a dual catalytic inhibitor of Topoisomerase I and II. This inhibition induces DNA damage and activates the cGAS-STING signaling pathway, leading to the production of type I interferon and chemokines CCL5 and CXCL10. Ru-4 demonstrates potent cytotoxicity in vitro and elicits a robust antitumor immune response in vivo. Furthermore, Ru-4 exhibits a synergistic antitumor growth effect when combined with a PD-1 inhibitor. To the best of our knowledge, this study is the first to demonstrate how rationally designed ruthenium(II) complexes can promote a chemoimmunotherapeutic response via the activation of the cGAS-STING pathway through the dual catalytic inhibition of topoisomerases. It is thus expected to pave the way for the development of new chemoimmunotherapy strategies.

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