Copper-induced injectable hydrogel with nitric oxide for enhanced immunotherapy by amplifying immunogenic cell death and regulating cancer associated fibroblasts

Shuilin Shen; Zimeng Zhang; Haixiao Huang; Jing Yang; Xinyue Tao; Zhengjie Meng; Hao Ren; Xueming Li

doi:https://doi.org/10.1186/s40824-023-00389-4

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자료유형: 학술저널

저자정보: Shuilin Shen (School of Pharmaceutical Science Nanjing Tech University) Zimeng Zhang (School of Pharmaceutical Science Nanjing Tech University) Haixiao Huang (School of Pharmaceutical Science Nanjing Tech University) Jing Yang (School of Pharmaceutical Science Nanjing Tech University) Xinyue Tao (School of Pharmaceutical Science Nanjing Tech University) Zhengjie Meng (School of Pharmaceutical Science Nanjing Tech University) Hao Ren (School of Pharmaceutical Science Nanjing Tech University) Xueming Li (School of Pharmaceutical Science Nanjing Tech University)

저널정보: 한국생체재료학회 생체재료학회지 생체재료학회지 제27권

발행연도: 2023.3

수록면: 1,219 - 1,240 (22page)

DOI: https://doi.org/10.1186/s40824-023-00389-4

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BackgroundImmunogenic cell death (ICD) induced by different cancer treatments has been widely evaluated to recruit immune cells and trigger the specific antitumor immunity. However, cancer associated fibroblasts (CAFs) can hinder the invasion of immune cells and polarize the recruited monocytes to M2-type macrophages, which greatly restrict the efficacy of immunotherapy (IT). MethodsIn this study, an injectable hydrogel induced by copper (Cu) has been designed to contain antibody of PD-L1 and nitric oxide (NO) donor. The therapeutic efficacy of hydrogel was studied in 4T1 cells and CAFs in vitro and 4T1 tumor-bearing mice in vivo. The immune effects on cytotoxic T lymphocytes, dendritic cells (DCs) and macrophages were analyzed by flow cytometry. Enzyme-linked immunosorbent assay, immunofluorescence and transcriptome analyses were also performed to evaluate the underlying mechanism. ResultsDue to the absorbance of Cu with the near-infrared laser irradiation, the injectable hydrogel exhibits persistent photothermal effect to kill cancer cells. In addition, the Cu of hydrogel shows the Fenton-like reaction to produce reactive oxygen species as chemodynamic therapy, thereby enhancing cancer treatment and amplifying ICD. More interestingly, we have found that the released NO can significantly increase depletion of CAFs and reduce the proportion of M2-type macrophages in vitro. Furthermore, due to the amplify of ICD, injectable hydrogel can effectively increase the infiltration of immune cells and reverse the immunosuppressive tumor microenvironment (TME) by regulating CAFs to enhance the therapeutic efficacy of anti-PD-L1 in vivo. ConclusionsThe ion induced self-assembled hydrogel with NO could enhance immunotherapy via amplifying ICD and regulating CAFs. It provides a novel strategy to provoke a robust antitumor immune response for clinical cancer immunotherapy.

#Injectable hydrogel #Nitric oxide #Immunotherapy #Immunogenic cell death #Cancer associated fbroblast

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