Rationale:
Ferroptosis drugs inducing cancer immunogenic cell death (ICD) have shown the potential of immunotherapy
in vivo
. However, the current ferroptosis drugs usually induce the insufficient immune response because of the low ROS generation efficiency.
Methods:
Herein, we design zinc-fluorouracil metallodrug networks (Zn-Fu MNs), by coordinating Zn and Fu via facile one-pot preparation, to inactivate mitochondrial electron transport for enhanced ROS production and immune activation.
Results:
Zn-Fu MNs can be responsive toward acidity and adenosine triphosphate (ATP) with the release of Fu and Zn
2+
, during which Zn
2+
can induce mitochondrion disruption to produce ROS, resulting in ferroptosis of cancer cells and 5-Fu interferes with DNA synthesis in nuclei with
19
F-MRI signal to be switched on for correlating drug release. With the synergistic effect of DNA damage and ferroptosis, the cancer cells are forced to promote ICD. Thereby, Zn-Fu MNs exhibit the excellent immune response without any other antigens loading. As a result, the infiltration of T cells within tumor and activation of immune cells in spleen have been greatly enhanced.
Conclusions:
Combined DNA damage and ferroptosis, Zn-Fu MNs induce the violent emission of tumor associated antigens within cancer cells which will sensitize naive dendritic cells and promote the activation and recruitment of cytotoxic T lymphocytes to exterminate cancer cells. Therefore, the obtained Zn-Fu MNs as ferroptosis inducers can effectively remodel immunosuppressive tumor microenvironment and activate antitumor immune reaction.