Nrf2 silencing amplifies DNA photooxidative damage to activate the STING pathway for synergistic tumor immunotherapy

Photodynamic therapy (PDT)-mediated antitumor immune response depends on oxidative stress intensity and subsequent immunogenic cell death (ICD) in tumor cells, yet the inherent antioxidant system restricts reactive oxygen species (ROS)-associated oxidative damage, which is highly correlated with the...

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Published inBiomaterials Vol. 296; p. 122068
Main Authors Sun, Shengjie, Yu, Mian, Yu, Liu, Huang, Wenxin, Zhu, Meishu, Fu, Yanan, Yan, Lingchen, Wang, Qiang, Ji, Xiaoyuan, Zhao, Jing, Wu, Meiying
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier Ltd 01.05.2023
Subjects
Cell Line, Tumor
DNA - metabolism
DNA oxidative damage
Glutathione - metabolism
Immunogenic cell death
Immunotherapy
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Oxidative Stress
Photoimmunotherapy
Reactive Oxygen Species - metabolism
siRNA delivery
STING pathway
Photoimmunotherapy
siRNA delivery
DNA oxidative damage
STING pathway
Immunogenic cell death
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Summary:Photodynamic therapy (PDT)-mediated antitumor immune response depends on oxidative stress intensity and subsequent immunogenic cell death (ICD) in tumor cells, yet the inherent antioxidant system restricts reactive oxygen species (ROS)-associated oxidative damage, which is highly correlated with the upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and the downstream products, such as glutathione (GSH). Herein, to overcome this dilemma, we designed a versatile nanoadjuvant (RI@Z-P) to enhance the sensitivity of tumor cells to oxidative stress via Nrf2-specific small interfering RNA (siNrf2). The constructed RI@Z-P could significantly amplify photooxidative stress and achieve robust DNA oxidative damage, activating the stimulator of interferon genes (STING)-dependent immune-sensing to produce interferon-β (IFN-β). Additionally, RI@Z-P together with laser irradiation reinforced tumor immunogenicity by exposing or releasing damage-associated molecular patterns (DAMPs), showing the prominent adjuvant effect for promoting dendritic cell (DC) maturation and T-lymphocyte activation and even alleviating the immunosuppressive microenvironment to some extent.
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ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2023.122068