Long-Lived Immunogenic Cell Death Induced by a Water-Soluble Redox Active Au(I) Bis-N-Heterocyclic Carbene.

Immunogenic cell death (ICD) is a form of regulated cell death that engages the immune system by releasing damage-associated molecular patterns, making it a promising target for cancer immunotherapy. Presented here is the synthesis and evaluation of a series of asymmetric redox-active water-soluble Au(I) bis-N-heterocyclic carbenes (Au(I) bis-NHCs). We explore the structure-activity relationships between redox activity, water solubility and ICD induction, building on our previous work with a redox-active Au(I) bis-NHC () that effectively induced ICD but suffered from poor water solubility. To overcome this limitation, we synthesized several water-soluble redox-active Au(I) bis-NHCs, derivatives , by modifying the imidazole moiety. Compound was identified as the lead, balancing water solubility and ICD induction efficacy. This compound, featuring a naphthoquinone moiety, and was found to generate reactive oxygen species (ROS) and trigger key ICD biomarkers, including calreticulin (CRT) translocation, ATP release, and high mobility group box 1 (HMGB1) secretion. A control compound lacking the redox active naphthoquinone failed to elicit these ICD markers or promote ROS production. Across the series a correlation was observed between ROS generation and ICD biomarker expression. In vivo studies in syngeneic immunocompetent mice demonstrated that compound not only prevents CT26 colorectal cancer tumor growth upon challenge with live cancer cells but also elicits a long-lived immune response upon rechallenge 12 months later.