Synergistic Reinforcing of Immunogenic Cell Death and Transforming Tumor-Associated Macrophages Via a Multifunctional Cascade Bioreactor for Optimizing Cancer Immunotherapy.

Immunogenic cell death (ICD) has aroused widespread attention because it can reconstruct a tumor microenvironment and activate antitumor immunity. This study proposes a two-way enhancement of ICD based on a CaO 2 @CuS-MnO 2 @HA (CCMH) nanocomposite to overcome the insufficient damage-associated molecular patterns (DAMPs) of conventional ICD-inducers. The near-infrared (NIR) irradiation (1064 nm) of CuS nanoparticles generates 1 O 2 through photodynamic therapy (PDT) to trigger ICD, and it also damages the Ca 2+ buffer function of mitochondria. Additionally, CaO 2 nanoparticles react with H 2 O to produce a large amount of O 2 and Ca 2+ , which respectively lead to enhanced PDT and Ca 2+ overload during mitochondrial damage, thereby triggering a robust ICD activation. Moreover, oxidative-damaged mitochondrial DNA, induced by PDT and released from tumor cells, reprograms the immunosuppressive tumor microenvironment by transforming tumor-associated macrophages to the M1 subphenotype. This study shows that CCMH with NIR-II irradiation can elicit adequate DAMPs and an active tumor-immune microenvironment for both 4T1 and CT26 tumor models. Combining this method with an immune checkpoint blockade can realize an improved immunotherapy efficacy and long-term protection effect for body.