GPX4-Targeting Phenolato ZrIV Complexes Induce Ferroptosis and Lysosome-Dependent Cell Death for Immunotherapy of Chemoresistant Cancer.

Here, we report three classes of dipicolinic acid (Dipic)-stabilized diaminobis(phenolato) ZrIV bis-chelates with high aqueous stability and potent antiproliferative activity. Among them, complex 1t exhibited strong cytotoxicity against multiple cancer cell lines, including cisplatin-resistant Hep G2/DDP cells, while showing low toxicity toward normal LO2 cells. Mechanistic studies demonstrated that 1t preferentially accumulates in mitochondria and lysosomes, leading to excessive ROS generation, lipid peroxidation, mitochondrial membrane depolarization, and GPX4 downregulation, consistent with ferroptosis induction. Concurrently, lysosomal iron accumulation, membrane permeabilization, and CTSB/caspase-8 activation indicated the involvement of lysosome-dependent cell death, further exacerbating oxidative stress. Moreover, 1t triggered immunogenic cell death and activated cGAS-STING signaling. In vivo, 1t significantly suppressed tumor growth in a Hep G2/DDP xenograft model with minimal systemic toxicity, highlighting Dipic-stabilized ZrIV bis-chelates as promising candidates for the treatment of chemoresistant cancers.