Bioinspired Construction of Cu–Fe Bimetallic Multienzyme Mimetics as Co-Inducers of Cuproptosis and Ferroptosis

Metalloenzyme mimics based on small
molecules are valuable
therapeutic
candidates, but there are few reports on their mechanism of action.
Inspired by natural enzymes, we designed two Cu–Fe bimetallic
multienzyme mimetics (CuFc1 and CuFc2).
Due to the coordination of the bimetallic centers, CuFc1 exhibits mimetic activities for multiple enzymes, including peroxidase
(POD), catalase (CAT), superoxide dismutase (SOD), and glutathione
oxidase (GSHOx). CuFc1 can catalyze cascade reactions
from •O2– and H2O2 to O2 and •OH, which leads to a storm of
reactive oxygen species and causes cuproptosis and ferroptosis in
cancer cells simultaneously. As CuFc1 treatment upregulates
the expression of PD-L1, it acts synergistically with the PD-L1 inhibitor
(BMS-1) to remodel the tumor immune microenvironments and stimulates
intense anticancer immune responses in vivo. In summary, through reasonable
molecular design, we first demonstrate the enormous potential of metallo
small molecule-based multienzyme mimics in cancer immunotherapy.