Fe/Mo‐Based Lipid Peroxidation Nanoamplifier Combined with Adenosine Immunometabolism Regulation to Augment Anti‐Breast Cancer Immunity

Abstract Immunogenic cell death (ICD)‐mediated immunization strategies have great potential against breast cancer. However, traditional strategies neglect the increase in the immunosuppressive metabolite, adenosine (ADO), during ICD, leading to insufficient therapeutic outcomes. In this study, it is found that the adenosine A2A receptor (A2AR) is significantly expressed in breast cancer and positively associated with regulatory T (Treg) cells. Herein, a strategy combining Fe/Mo‐based lipid peroxidation (LPO) nanoamplifiers and A2AR blockade is reported to maximize ICD‐mediated anti‐tumor immunity. This LPO nanoamplifier causes LPO explosion by the Fe (II)‐mediated Fenton reaction and Mo(V)‐mediated Russell mechanism. Subsequently, it elicits the ICD magnification of tumor cells by inducing multiple regulated cell death patterns of ferroptosis, apoptosis, and necroptosis. Additionally, the A2AR antagonist (SCH58261), an immunometabolic checkpoint blocker, is found to relieve ADO‐related immunosuppression, amplify anti‐tumor immunological effects, and elicit immune memory responses. This robust anti‐tumor immunity is observed in primary, distant, pulmonary metastatic, and recurrent tumors. This study provides a novel strategy for optimizing ICD‐mediated immunotherapy and highlights the benefits of combining LPO explosion with A2AR blockade to enhance breast cancer immunotherapy.