Abstract
Ferroptosis is recognized as a form of regulated cell death characterized by iron-dependent lipid peroxidation and significant immunogenic properties. However, we observe that the hypoxic tumor microenvironment (TME) of solid tumors severely limits ferroptosis induction and antitumor immune responses, while simultaneously promoting programmed death-ligand 1 (PD-L1) expression, thereby further compromising tumor immunotherapy. Herein, we exploit a fluorinated prodrug-engineered nano-remodeler to reverse the hypoxic and immunosuppressive TME for enhancing ferroptosis/immunomodulation-driven antitumor therapy. The nano-remodeler is elaborately co-assembled by the disulfide-bonded fluorinated JQ1 prodrug (a PD-L1 inhibitor) and sorafenib (Sor, a ferroptosis inducer). As expected, the ferroptosis induction efficiency and antitumor immunogenicity of Sor are significantly improved due to oxygen supply in hypoxic solid tumors, resulting in a highly synergistic ferroptosis-immunotherapy with JQ1. As a result, this nano-remodeler exerts a potent tumor inhibitory effect in multiple tumor models. This study provides insights into the nanotherapeutic paradigm of tumor hypoxia intervention in multimodal ferroptosis-immunotherapy.