Ultrasound/pH dual-triggered MnO2 nanoplatform synergizes with SDT to boost anti-tumor immunity via macrophage repolarization in non-small cell lung cancer

Immune checkpoint blockade (ICB) is the first-line treatment for non-small cell lung cancer (NSCLC); however, its clinical benefit is severely limited by primary resistance and low response rates. Tumor-associated macrophages (TAMs) predominantly polarize toward the pro-tumor M2 phenotype, and cancer cells evade phagocytic clearance via the CD47-SIRPα “don’t eat me” axis. We developed an ultrasound and pH dual-triggered MnO 2 -based nanoparticles (PHshC NPs) that co‑delivers CD47 shRNA and Ce6 and is surface‑decorated with cyclic arginine‑glycine‑aspartic acid for active tumor targeting. CD47 silencing by the shRNA effectively blocked the “don’t eat me” axis, thereby enhancing macrophage phagocytosis and dendritic cell antigen presentation. Concurrent ultrasound‑triggered sonodynamic therapy (SDT) induced immunogenic cell death, releasing tumor antigens. In vivo, the nanocomposite induced M2-to-M1 macrophage repolarization, promoted dendritic cell maturation, and enhanced CD8 + T cell activation via STING‑ associated signaling, producing robust antitumor efficacy without observable systemic toxicity. Integrative transcriptomic and proteomic analyses provided evidence that PHshC NPs combined with US treatment globally reprogrammed the tumor immune landscape and activated coordinated innate and adaptive antitumor immune responses. This multifunctional platform integrated genetic engineering, SDT, and enhancing antitumor immune responses into a single dual-triggered nanoplatform, serving as a highly promising multimodal intervention for reshaping the immune microenvironment in NSCLC.