2025/12/08 by Jun Shu, Xianbo Wu, Zixin Tang +5 · 1 voice · 11 citations
Biochemistry, Genetics and Molecular Biology · Engineering · Immunology and Microbiology · #Apoptosis #Cancer cell #Cytotoxicity #Immune system #Immunogenic cell death #Immunotherapy #Inflammasome and immune disorders #Innate immune system #Nanoplatforms for cancer theranostics #Programmed cell death #interferon and immune responses
paper · open access · doi:10.1002/anie.202521242
published in Angewandte Chemie International Edition 65(5), e21242 (Wiley)
openalex created_date 2025/12/08 · openalex publication_date 2025/12/08 · openalex updated_date 2026/08/05
Most clinically used chemotherapeutic agents act by inducing apoptosis. However, their clinical effectiveness is often limited by poor therapeutic efficacy and the rapid development of drug resistance. In contrast, oncosis, as an inflammatory form of cell death independent of adenosine triphosphate (ATP) and apoptotic pathways, exhibits unique advantages in overcoming tumor drug resistance and regulating anti-tumor immune responses. Herein, we present the first iridium(III)-based immunogenic oncosis inducers designed to concurrently induce oncosis and activate the cGAS-STING pathway, thereby bridging chemotherapy with immunotherapy. Through a bioisosteric design strategy, we identified benzoselenazole and benzothiazole derivatives as key pharmacophores for triggering oncosis. These iridium(III)-based oncosis-inducers rapidly disrupt mitochondrial architecture, induce oxidative stress, and promote Ca(II) release, which subsequently activate calpain and porimin to initiate oncosis in multidrug-resistant cancer cells. Transcriptomic profiling further revealed their ability to regulate actin cytoskeleton organization, modulate ABC transporter activity, and affect glycolysis/gluconeogenesis. Notably, the metal complexes induce mitochondrial swelling and mt-DNA damage, leading to robust activation of the cGAS-STING innate immune pathway and eliciting a strong anticancer immune response. Based on these multimodal mechanisms, the Ir(III)-based immunogenic oncosis inducers were able to effectively kill drug-resistant cancer cells and enhance the anticancer immune response in tumor mouse models.