Ruthenium(II) complex enhances anti-breast cancer immune responses by inducing pyroptosis and immunogenic cell death while activating the cGAS-STING pathway.

Cancer immunotherapy has revolutionized oncological treatment by exhibiting potent antitumor efficacy and durable therapeutic responses across a broad spectrum of malignancies. In the present study, three novel Ru(II) complexes (Ru1, Ru2, and Ru3) were rationally designed, synthesized, and systematically characterized. In vitro antitumor evaluations demonstrated that all three Ru(II) complexes exerted pronounced cytotoxic effects against cancer cells. Among them, Ru3 exhibited superior biological activity, rapidly entering MCF-7 cells through an endocytosis-mediated pathway while simultaneously accumulating within both mitochondria and the endoplasmic reticulum. Mechanistic investigations revealed that Ru3 induced significant S-phase cell cycle arrest and subsequently triggered pyroptotic cell death in tumor cells. More importantly, Ru3 effectively initiated immunogenic cell death (ICD) and activated the cGAS-STING signaling pathway, thereby amplifying antitumor immune responses. Subsequent in vivo studies further demonstrated that Ru3 markedly increased the ratio of dendritic cells to CD8+ T cells, enhanced effector T-cell activity, and reduced the proportion of immunosuppressive regulatory T cells (Tregs) in mice, which in turn activated host antitumor immunity. Collectively, these findings indicate that Ru3 integrates direct tumoricidal activity with immune modulation, highlighting its considerable potential as a multifunctional Ru-based anticancer candidate for cancer immunotherapy.