Organelle-Targeting Iridium(III) Benzothiazole Complexes Potently Induce Immunogenic Cell Death for Gastric Cancer Immunotherapy

Despite being the mainstay for gastric cancer treatment, conventional therapies such as surgery, chemotherapy, and radiotherapy suffer from substantial limitations that compromise their efficacy and patients’ quality of life. To overcome these challenges, innovative strategies and novel combination therapies are urgently needed. Herein, we report a series of organelle-targeting iridium(III) benzothiazole complexes designed to localize in mitochondria, lysosomes, the endoplasmic reticulum, and the Golgi apparatus. Among them, the mitochondria- and lysosome-targeting complexes demonstrated potent cytotoxicity against gastric cancer cells and induced distinct nonapoptotic cell death pathways, ultimately leading to immunogenic cell death. Given the inadequacy of conventional methods to decipher the immunomodulatory effects of metallodrugs in the tumor immune microenvironment (TME), we employed time-of-flight mass cytometry (CyTOF) to achieve a comprehensive profiling of immune cell subsets. This work provides a multidimensional characterization of TME remodeling by organelle-targeted Ir(III) complexes, offering valuable insights for developing metal-based chemoimmunotherapeutics.