Ferroptosis Amplifier Remodels Redox Homeostasis for Enhanced Cancer Chemoimmunotherapy

Despite the tremendous therapeutic promise of immune checkpoint blockade (ICB), it benefits only a minority of cancer patients due to the poor immunogenicity of solid tumors. Several chemotherapeutic agents can induce immunogenic cell death (ICD) to synergize with ICB, whereas abnormal redox homeostasis in a tumor microenvironment (TME) restricts the chemotherapy-induced ICD effect. Herein, we report a Cu-based ferroptosis amplifier (Cu-POX) for enhanced cancer immunotherapy by remodeling redox homeostasis and increasing ICD induction. In the TME, glutathione depletion triggers a series of responsive behaviors, resulting in the exaltation of oxidative stress and the induction of ferroptosis. More importantly, a powerful ICD cascade activates immunogenicity in the TME and in turn reinforces the efficacy of anti-PD-L1 antibody (aPD-L1)-mediated ICB therapy. In tumor-bearing mouse models, Cu-POX synergized with ICB therapy exhibited a robust inhibitory effect of bilateral subcutaneous tumors and activated a long-term immune memory effect. This work shows a ferroptosis-amplifying system enhanced by cascade responses for cancer immunotherapy.