Nanoscale Metal–Organic Frameworks‐Mediated Degradation of Mutant p53 Proteins and Activation of cGAS‐STING Pathway for Enhanced Cancer Immunotherapy

Abstract 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.