Three Is Better than One: A Multimetal Complex that Triggers Immunogenic Cell Death

Immunogenic cell death (ICD) is a form of regulated cell death capable of stimulating an adaptive immune response through release of damage-associated molecular patterns (DAMPs). While several metal complexes have shown promise as ICD inducers, conjugates containing more than one metal center remain to be explored for ICD. Here, we report the design, synthesis, and evaluation of a tri-metallic Au^I-Pt^IV-Ru^II prodrug (5) that codelivers oxaliplatin (Type I ICD inducer), Ru^II arene 2-pyridinecarbothioamides (Type I), and Au(I) bis-N-heterocyclic (Type II) using a single scaffold. Upon reduction, complex 5 releases all three cytotoxic species, resulting in enhanced inhibition of thioredoxin reductase (TrxR1&2), elevated production of reactive oxygen species (ROS), and in vitro DAMP release. In vivo studies of complex 5 in a colorectal cancer mouse model demonstrated tumor growth suppression, reduced off-target metal accumulation, and improved immune memory in a tumor challenge study compared to a 1:1:1 mixture of the constituent agents. Furthermore, peripheral white blood cell (WBC) profiling revealed that complex 5 activates both the innate and adaptive immune compartments. This study demonstrates an integrated chemo-immunotherapeutic strategy that unifies multiple ICD triggers within a single prodrug framework. It thus highlights a promising approach to the creation of metal-based multimodal anticancer therapies.