A mitochondria-targeted iridium complex activates anti-tumour immunity by regulating zinc homeostasis in cancer cells and macrophages

Abstract

Intracellular zinc homeostasis and subcellular compartmentalization are exquisitely regulated, playing critical roles in immune regulation, such as inducing inflammatory programmed cell death, producing high levels of interferons and inflammatory cytokines, controlling the polarization and function of macrophages, etc. Herein, we designed two cyclometalated Ir(III) complexes with moderate zinc ion (Zn²⁺) affinity, capable of re-distributing the endogenous Zn²⁺ from the cytoplasm and vesicles to mitochondria as indicated by ICP-MS measurement, thus inducing mitochondrial dysfunction and apoptosis. Moreover, mitochondria-targeted Ir2 also displayed better immunoregulation activity than lysosome-targeted Ir1, capable of triggering GSDMD-mediated pyroptosis via caspase-1 dependent pathway and down-regulating PD-L1 levels in cancer cells. In macrophages, Ir2 also re-distributed intracellular zinc effectively, leading to an increased zinc level in mitochondria and promoting the M0-to-M1 polarization of macrophages. The antitumor efficacy and immunoregulation activity were also verified in vivo. This work suggested that the modulation of endogenous zinc homeostasis both in cancer cells and immune cells would be a promising strategy for activating anti-tumour immunity, and provided new clues for designing novel metallodrugs for cancer chemo-immunotherapy.