An Fe(III)-covalent organic framework (COF)-sorafenib nanoplatform induces chemo-ferroptosis for enhanced hepatocellular carcinoma immunotherapy.

Chemoresistance remains a tremendous challenge in the clinical treatment of hepatocellular carcinoma (HCC). However, the induction of ferroptosis, a form of regulated cell death, could overcome chemoresistance and improve treatment outcomes for HCC patients. In this study, we constructed a covalent organic framework (COF)-based nanoplatform (SRF@Fe(III)-COF) that combines ferroptosis induction and chemotherapy for dual-mode HCC treatment. The peroxidase- and glutathione oxidase-like activities of the nanoplatform are mediated by ferric (Fe(III)) ions, which act as excellent ferroptosis executors, and the encapsulated sorafenib (SRF) can attenuate tumor cell resistance to ferroptosis, effectively facilitating chemo-ferroptosis. Furthermore, SRF@Fe(III)-COF was found to trigger immunogenic cell death and stimulate a pronounced immune response by inducing robust ferroptosis. SRF@Fe(III)-COF synergized with programmed death receptor-1 (PD-1) immune checkpoint blockade to effectively restrict the growth of primary and distal H22 tumors by recruiting tumor-infiltrating lymphocytes and establishing systemic immune memory. Overall, our study revealed that the combination of a chemotherapeutic agent with a ferroptosis inducer is a promising approach for improving HCC immunotherapy.