A Ferroptosis Amplification Loop Induced by Compensatory Nanomedicine Enhances Breast Cancer Immunotherapy

Tumor cells often develop compensatory mechanisms to evade antitumor therapies, thereby diminishing therapeutic efficacy. In this work, a self-delivering compensatory nanomedicine (designated as a BRC) is developed to amplify ferroptotic cell death and potentiate αPD-L1 therapy in breast cancer. By optimizing intermolecular interactions, the dihydroorotate dehydrogenase (DHODH) inhibitor brequinar (Bre), the ferroptosis inducer RSL3, and the photosensitizer chlorin e6 (Ce6) are coassembled into a uniform and stable nanostructure without the need for additional carriers. Upon light activation, BRC initiates photodynamic therapy (PDT)-induced lipid peroxidation, which synergizes with GPX4 inhibition and disruption of the DHODH-mediated compensatory pathway, thereby establishing a ferroptosis-amplifying loop that triggers potent ferroptotic cell death. As a result, BRC not only suppresses primary tumor growth but also significantly enhances tumor immunogenicity. Moreover, in combination with the αPD-L1 blockade, BRC effectively activates both innate and adaptive immune responses, resulting in the eradication of metastatic tumors without observable systemic toxicity. This work presents a compelling strategy that targets compensatory resistance mechanisms to induce ferroptotic cell death, offering a promising approach to potentiating breast cancer immunotherapy.