Activated Dendritic Cell Membrane‐Engineered Nanoformulation of Metallo‐Immunomodulators as Lysosome‐Targeted Adjuvants for Synergistic Cancer Immunotherapy

Abstract Combination of chemotherapy and cancer immunotherapy has shown substantial clinical promise. However, the immunosuppressive tumor microenvironment (TME) poses a critical barrier to this combination therapy. Here, a tumor lysosome‐targeted immunomodulatory strategy based on a biomimetic nanoadjuvant is presented, which effectively overcomes the immunosuppressive TME and demonstrates enhanced therapeutic efficacy when combined with chemotherapy. This nanoadjuvant integrates Fe‐DOX coordination nanoparticles, a MnCO 3 shell, TLR7/8 agonist (R848), and a mature dendritic cell membrane (DCM) coating. The resulting DCM@(Fe‐DOX‐Mn‐R848) nanoadjuvant induces immunogenic cell death in tumor cells via lysosomal‐mitochondrial cascade destruction. Concurrently, it activates the cGAS‐STING signaling pathway to promote dendritic cell maturation and repolarize tumor‐associated macrophages from M2 to M1 phenotype, thereby effectively enhancing CD8 + T cell activation and tumor therapeutic efficacy. When combined with PD‐L1 blockade therapy, the nanoadjuvant demonstrates enhanced efficacy in murine models of primary and recurrent triple‐negative breast cancer, establishing durable immune memory. This platform demonstrates significant potential in overcoming immunosuppressive TME and advancing combination therapy through lysosome‐targeting drug delivery technology, revealing promising prospects for cancer treatment.