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 MnCO₃ 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.