Breast cancer represents one of the most prevalent malignancies worldwide. Despite significant advances in breast cancer management, triple-negative breast cancer (TNBC) remains challenging due to its low cure rate, high recurrence, and metastatic potential, with limited effective therapies currently available [1], [2]. Platinum complexes, represented by cisplatin, have played a significant role in clinical chemotherapy. Inspired by cisplatin, the potential of a large number of metal complexes for tumor treatment has been explored. Transition metal iridium(III) and ruthenium(II) complexes exhibit unique characteristics including structural diversity, ligand exchange capability, redox properties, and catalytic activity, rendering them promising anticancer candidates [3], [4]. These complexes have demonstrated therapeutic potential across multiple cancer types, including breast, cervical, colorectal, glioblastoma, and lung cancers [5], [6], [7].

Accumulating clinical evidence indicates that conventional chemotherapeutic agents not only exert direct cytotoxic effects on rapidly proliferating cancer cells but also reactivate tumor-specific immune responses [8], [9]. Several clinically established chemotherapeutic agents, including doxorubicin, cyclophosphamide, and oxaliplatin, demonstrate promising immunogenic cell death (ICD) activity [10], [11]. The potential of transition metal iridium(III) and ruthenium(II) complexes in the field of tumor immunotherapy has also been explored. For instance, Chao et al. designed and synthesized the first iridium(III) complex capable of inducing ICD [12]. Wang et al. reported a nuclear-targeting ruthenium(II) complex that induces ICD in melanoma cells and enhances anti-PD-1 immunotherapy by remodeling the tumor microenvironment in mice [13]. In addition, in recent years, it has been reported that iridium(III) or ruthenium(II) complexes can cause diverse tumor cell death modalities, including pyroptosis [14], [15], necroptosis [16], [17], ferroptosis [18], [19], autophagy [20], [21], paraptosis [22], [23], and necrosis [24], [25].

Vadimezan (VDA) is a vascular blocker and the first discovered potent small molecule mouse derived stimulator of interferon genes (STING) agonist [26], [27], [28]. It exhibits anti-tumor and antiviral activities and is often used in combination with other drugs such as cisplatin, cyclosporine, and paclitaxel for the treatment of advanced lung cancer and other tumors, demonstrating the advantages of high efficacy and few side effects [29], [30]. The cGAS (cyclic GMP-AMP synthase)-STING signaling pathway serves as an essential component of innate immunity and plays a crucial role in immunotherapy [31]. Accumulating evidence indicates that activation of the cGAS-STING signaling pathway is beneficial for tumor killing immunity [32]. Co-delivery of chemotherapeutic SN38 and STING agonist VDA via nanosystems elicits robust STING-mediated antitumor immunity in multiple murine models [33]. Several studies have reported synergistic effects from STING agonist-metal complex conjugates. Platinum(IV)-MSA-2 conjugates have been reported to enhance natural killer (NK) cell tumor infiltration and promote activation of T cells, NK cells, and dendritic cells within tumor tissue [34]. However, VDA-metal conjugates remain unreported, particularly those involving phosphorescent octahedral iridium(III) and ruthenium(II) complexes.

Inspired by these findings, three iridium(III) (Ir-VDA-1–3) and three ruthenium(II) (Ru-VDA-1–3) complexes were obtained by conjugating the STING agonist VDA with iridium(III) and ruthenium(II) precursors, respectively. The structures of these complexes are illustrated in Scheme 1. Mechanistic studies confirmed that Ir-VDA-1–3 localize to mitochondria, induce mitochondrial membrane potential (MMP) depolarization, generate excessive reactive oxygen species (ROS), arrest cell cycle progression, and concurrently induce both pyroptosis and apoptosis. Further investigations revealed that Ir-VDA-1–3 not only activate the cGAS-STING signaling pathway but also induce ICD, thereby exerting antitumor immunotherapeutic effects.