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Ferroptosis, an uncommon nonapoptotic cell loss of life brought on by iron-dependent accumulation of lipid peroxide, allows versatile design of antitumor platform. Particularly, as a constructive function, ferroptosis can induce immune response accompanied with the interferon-γ (IFN-γ)-triggered disruption of the glutathione peroxidase 4 pathway for cascade enhancement of ferroptotic cell loss of life and ferroptosis-induced immunotherapeutic efficacy. Nevertheless, as a unfavorable function, ferroptosis additionally triggers inflammation-associated immunosuppression by up-regulation of cyclooxygenase-2/prostaglandin E2 pathway and IFN-γ-associated adaptive immune resistance by up-regulation of programmed loss of life ligand-1 (PD-L1), impeding the antitumor efficacy of a number of immune cells by immune escape. Damaging and constructive roles endow ferroptosis with janus-faced nature. It’s pressing to control the janus-faced nature of ferroptosis for eliciting the maximized ferroptotic therapeutic efficacy. Herein, a self-amplifying nanodrug (RCH NPs) was designed by co-assembling hemin (ferric porphyrin), celecoxib (anti-inflammatory drug) and roscovitine (cyclin-dependent kinase 5 inhibitor) with the help of human serum albumin for reprograming janus-faced nature of ferroptosis. Throughout hemin-triggered ferroptosis, celecoxib disrupted the inflammation-related immunosuppression whereas roscovitine destroyed IFN-γ-induced up-regulation of PD-L1 by genetic blockade impact. The RCH NPs thus demonstrated superior therapeutic results on tumors, due to the self-amplifying ferroptotic immunotherapy. Our work gives a conceptually revolutionary technique for harnessing ferroptosis in opposition to tumors.
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