A Robust ROS Generation and Ferroptotic Lipid Modulation Nanosystem for Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy

Abstract Ferroptosis initiation is often utilized for synergistic immunotherapy. While, current immunotherapy is limited by an immunosuppressive tumor microenvironment (TME), and ferroptosis is limited by insufficient reactive oxygen species (ROS) and ferroptotic lipids in tumor cells. Here, an arachidonic acid (AA) loaded nanosystem (CTFAP) is developed to mutually reinforce ferroptosis and cancer immunotherapy by augmenting ROS generation and modulating ferroptotic lipids. CTFAP is composed of acid‐responsive core calcium peroxide (CaO 2 ) nanoparticles, ferroptotic lipids sponsor AA, tetracarboxylic porphyrin (TCPP) and Fe 3+ based metal‐organic framework structure, and biocompatible mPEG‐DSPE for improved stability. Once endocytosed by tumor cells, CTFAP can release oxygen (O 2 ) and hydrogen peroxide (H 2 O 2 ) in the acidic TME, facilitating TCPP‐based sonodynamic therapy and Fe 3+ ‐mediated Fenton‐like reactions to generate substantial ROS for cell ferroptosis initiation. The immunogenic cell death (ICD) after ferroptosis promotes interferon γ (IFN‐γ) secretion to up‐regulate the expression of long‐chain family member 4 (ACSL4), cooperating with the released AA from CTFAP to accelerate the accumulation of lipid peroxidation (LPO) and thereby promoting ferroptosis in cancer cells.CTFAP with ultrasound treatment efficiently suppresses tumor growth, has great potential to challenges in cancer immunotherapy.