Synergistic immunotherapy of NSCLC enabled by a biomimetic nanodelivery system for autophagy-mediated MDSC reprogramming and metabolic modulation.

Abstract

The immunosuppressive tumor microenvironment (TME) in non-small cell lung cancer (NSCLC), particularly the dominance of myeloid-derived suppressor cells (MDSCs), remains a major barrier to effective immunotherapy. Here, we developed a bioengineered nanoplatform (PD-L1-SSD@NPs) by conjugating an anti-PD-L1 antibody to hollow mesoporous silica nanoparticles for the targeted delivery of saikosaponin D (SSD) to PD-L1-high MDSCs. This strategy nanoplatform enhanced SSD delivery and activated autophagic flux in MDSCs, thereby reprogramming them from an immunosuppressive phenotype toward an immune-activating state. This reprogramming was characterized by reduced Arg-1, iNOS, and reactive oxygen species (ROS) levels, together with increased IL-12 and TNF-α expression. Functionally, PD-L1-SSD@NP-treated MDSCs restored the proliferation, activation, and cytokine-producing capacity of CD8⁺ T cells, while reducing exhaustion-associated marker expression. In an orthotopic Lewis lung carcinoma model, PD-L1-SSD@NPs inhibited tumor progression, reduced MDSC-mediated immunosuppression, enhanced CD8⁺ T-cell infiltration and effector function, and improved the preliminary biosafety and pharmacokinetic profile of SSD. Single-cell transcriptomic, proteomic, and metabolomic analyses further revealed enhanced T-cell cytotoxicity and reconfigured immunometabolic pathways after treatment. Importantly, 3-MA-mediated autophagy inhibition partially reversed the immune-remodeling effects of PD-L1-SSD@NPs, supporting an autophagy-dependent mechanism of MDSC reprogramming. Collectively, these findings highlight a targeted nanotherapeutic strategy that remodels the immunosuppressive niche through autophagy activation and offers a promising approach for overcoming resistance to cancer immunotherapy.