Fluorescent ferroptosis inducers leveraging the pharmacological activity of rhodanine to promote antitumor immunity
摘要
Ferroptosis, a form of unique cell death characterized by iron and iron-dependent accumulation of lipid peroxidation, has attracted increasing attention for cancer therapy. However, the antitumor efficacies of current small-molecule ferroptosis inducers are always not potent enough, and there is a debate over whether ferroptosis induces immunogenic or nonimmunogenic cell death. Guided by the pharmacophore concept, we rationally design a rhodanine-based small-molecule ferroptosis inducer, which can target the endoplasmic reticulum (ER) as a pivotal center for lipid metabolism. Metabolic and proteomic analyses suggest that the inducer causes dysregulation of cellular lipid metabolism, which can contribute to cell ferroptosis. In vivo results indicate that it triggers immunogenic cell death and activates the immune response to suppress tumor growth, accompanied by reversing the immunosuppressive tumor microenvironment and enhancing immunological memory. Furthermore, this inducer has an intrinsic photodynamic character that can further promote therapeutic efficacy with a single treatment. Specifically, the populations of CD8+ and CD4+ T cells in the spleen of tumor-bearing mice show a 3.2-fold and 2.6-fold increase upon treatment, respectively. Overall, this innovative approach has the potential to enhance antitumor therapies by exploiting the benefits of ferroptosis and immune activation, providing a working principle for further investigation of ferroptosis-based therapeutic strategies.