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, 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.