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.