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Nanoscale Metal–Organic Frameworks‐Mediated Degradation of Mutant p53 Proteins and Activation of cGAS‐STING Pathway for Enhanced Cancer Immunotherapy
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Nanoscale Metal–Organic Frameworks‐Mediated Degradation of Mutant p53 Proteins and Activation of cGAS‐STING Pathway for Enhanced Cancer Immunotherapy
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Journal Article
Nanoscale Metal–Organic Frameworks‐Mediated Degradation of Mutant p53 Proteins and Activation of cGAS‐STING Pathway for Enhanced Cancer Immunotherapy
2024
Overview
Activating cGAS‐STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance of the cGAS‐STING pathway. Herein, multifunctional ZIF‐8@MnO2 nanoparticles are constructed to degrade mutp53 and facilitate the cGAS‐STING pathway. The synthesized ZIF‐8@MnO2 can release Zn2+ and Mn2+ in cancer cells to induce oxidative stress and cytoplasmic leakage of fragmented mitochondrial double‐stranded DNAs (dsDNAs). Importantly, the released Zn2+ induces variable degradation of multifarious p53 mutants through proteasome ubiquitination, which can alleviate the inhibitory effects of mutp53 on the cGAS‐STING pathway. In addition, the released Mn2+ further increases the sensitivity of cGAS to dsDNAs as immunostimulatory signals. Both in vitro and in vivo results demonstrate that ZIF‐8@MnO2 effectively promotes the cGAS‐STING pathway and synergizes with PD‐L1 checkpoint blockades, leading to remarkable regression of local tumors as well as distant metastases of breast cancer. This study proposes an inorganic metal ion‐based nanoplatform to enhance the cGAS‐STING‐mediated antitumor immunotherapy, especially to those tumors with mutp53 expression. A nanotechnology‐based Mn–Zn dual‐ion delivery platform is constructed. It can enhance the cGAS‐STING‐mediated anti‐tumor immunotherapy via. multiple aspects, including GSH responsive, cGAS enzymatic activity‐modulated, and mutp53‐targeted manifold pathways. This study lays a foundation for designing therapeutic strategies targeting the cGAS‐STING pathway and offers new immunotherapeutic options for patients with overexpressed mutant p53.
