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

Abstract 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 CaO2@CuS–MnO2@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 1O2 through photodynamic therapy (PDT) to trigger ICD, and it also damages the Ca2+ buffer function of mitochondria. Additionally, CaO2 nanoparticles react with H2O to produce a large amount of O2 and Ca2+, which respectively lead to enhanced PDT and Ca2+ 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.