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

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, <b>Ru-4</b>, 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. <b>Ru-4</b> demonstrates potent cytotoxicity in vitro and elicits a robust antitumor immune response in vivo. Furthermore, <b>Ru-4</b> 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.