Sequential Tumor Microenvironment Reprogramming by Nanoplatform Potentiates Sonodynamic‐Chemodynamic Therapy and Immune Checkpoint Blockade in Breast Cancer

Abstract The complex tumor microenvironment (TME) remains a major barrier to effective breast cancer therapy. A modular nanoplatform capable of sequentially reprogramming the TME through cascade actions and responsive therapeutic functions is developed to enhance breast cancer immunotherapy. A hybrid nanoparticle (MCC) containing manganese dioxide (MnO 2 ), calcium peroxide (CaO 2 ), and chlorin e6 (Ce6) is synthesized and subsequently camouflaged with a tumor cell membrane. Surface conjugation of a PD‐L1 antibody (αP) is then achieved via a glutathione (GSH)‐responsive fragment, resulting in the formation of an integrated nanoplatform MCC@TM‐αP. Through dual‐targeting mechanisms involving the tumor cell membrane and the PD‐L1 antibody, MCC@TM‐αP achieves efficient enrichment at tumor sites. MCC@TM‐αP alleviates hypoxia by generating O 2 from CaO 2 in the acidic TME and scavenges GSH via the MnO 2 ‐mediated Fenton‐like reaction, thereby markedly amplifying the sonodynamic efficacy of Ce6. The combined effects of sonodynamic therapy and chemodynamic therapy ablate tumors and reprogram the immunosuppressive TME. Upon cleavage of the GSH‐responsive fragment by intratumoral GSH, MCC@TM‐αP releases the PD‐L1 antibody, eliciting a robust immune response that eradicates metastatic tumors. In murine breast cancer models, this therapeutic strategy enhances tumor infiltration by effector T cells and suppresses metastatic progression. By sequentially decoupling the immunosuppressive mechanisms, this study provides a programmable approach to potentiate immunotherapy and overcome TME‐driven resistance.