Oxoisoaporphine Half-Sandwich Osmium(II) Derivative: A Catalytic Trigger for Innate Tumor Chemoimmunotherapy

Abstract

Chemoimmunotherapy, particularly strategies that induce a tumor specific antitumor immune response, 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 half-sandwich osmium(II) complex, Os-1, which acts as a catalyst for H2O2 generation through autocatalytic hydride transfer from coenzyme NADH to oxygen. Sustained H2O2 self-supply generation disrupts tumor redox homeostasis and induces DNA damage, leading to the activation of the cGAS-STING signaling pathway. Os-1 demonstrates potent cytotoxicity in vitro and elicits a robust antitumor immune response in vivo. Furthermore, Os-1 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 describe the rational design of a small-molecule metal catalyst that provides for the in situ generation of H2O2 in cancer cells, thus overcoming the exogenous-additive bottleneck of oxidative therapy. This self-sufficient system not only promotes oxidative damage but also activates the cGAS-STING pathway, thereby integrating synergistically oxidative and immunotherapeutic actions.