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

• Published in: Advanced materials (Weinheim) Vol. 34; no. 51; pp. e2207593 - n/a
• Main Authors: Huang, Cong, Lin, Bingquan, Chen, Chuyao, Wang, Huaiming, Lin, Xiaosheng, Liu, Jiamin, Ren, Qingfan, Tao, Jia, Zhao, Peng, Xu, Yikai
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.12.2022
• Subjects: Apoptosis; Bioreactors; Calcium ions; calcium‐ion overload; Cell death; Cell Line, Tumor; Copper sulfides; Damage patterns; damage‐associated molecular patterns; Humans; Immunogenic Cell Death; Immunotherapy; Immunotherapy - methods; Irradiation; Macrophages; Manganese Compounds; Manganese dioxide; Materials science; Mitochondria; Mitochondrial DNA; Nanocomposites; Nanoparticles; Near infrared radiation; Neoplasms - therapy; Oxides - pharmacology; Photochemotherapy - methods; Photodynamic therapy; Tumor Microenvironment; Tumor-Associated Macrophages; calcium-ion overload; damage-associated molecular patterns; photodynamic therapy; immunotherapy; tumor-associated macrophages
• ISSN: 0935-9648; 1521-4095; 1521-4095
• DOI: 10.1002/adma.202207593

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. A CaO2@CuS–MnO2@HA (CCMH) nanocomposite is developed to achieve the two‐way enhancement of Ca2+ overload and photodynamic therapy related immunogenic cell death, by disrupting the mitochondrial Ca2+ buffering capacity and allaying hypoxia. Moreover, the subsequently escaped oxidatively damaged mitochondrial DNA is able to activate M1 polarization of tumor associated macrophages. Combining CCMH with aPD‐L1 significantly improves immunotherapy efficacy.