Promoting innate immunity by inducing pyroptosis or cyclic GMP-AMP synthetase to stimulate the activation of interferon gene (CGAS-sting) pathway has become an effective way to fight the immunosuppressive tumor microenvironment and elicit systemic anti-tumor immunity. However, current pyroptosis inducers and STING agonists have limitations, including instability and non-instabilityInstitute of Chemistry, Chinese Academy of SciencesXiao HaihuaProfessor, Xiangya Hospital, Central South UniversityLiu ZhaoqianProfessors andMao XiaoyuanTeam of professorsA tumor-specific nano** platform was constructed, which combined photodynamic (PDT) with epigenetic** to simultaneously activate pyroptosis and CGAS-STING pathways in a photocontrolled manner. The study, titled "Simultaneous activation of pyroptosis and cgas-sting pathway with epigenetic photodynamic nanotheranostic for enhanced tumor photoimmunotherapy," was published in Advanced Materials.
In this study, the nano** platform constructed by the authors consists of oxidation reaction nanoparticles (NP1) containing the photosensitizer TBE and nanoparticles (NP2) containing DNA methyltransferase inhibitors (DNMTI). The aim is to convert immunoindolent (cold) breast tumors into immunogenic (hot) tumors by simultaneously inducing pyroptosis and activating the cgassting pathway in a photocontrolled manner. As shown in Figure 1, DNTIs released by NP2 can restore intracellular STING and GSDME expression by pharmacologically inhibiting promoter hypermethylation, while the photodynamic effect of NP1 can activate caspase-3 cleavage of upregulated GSMDE, producing GSDME-N-terminus for pyroptosis.
In addition, photodynamic ** (PDT)-induced production of reactive oxygen species (ROS) can lead to mitochondrial dysfunction, leading to cytosolic release of mitochondrial DNA (mtDNA) and subsequent activation of the CGAS-STING signaling pathway. Therefore, activate at the same time.
Pyroptosis and intracellular CGAS-STING signaling pathways trigger the release of pro-inflammatory cytokines and promote the maturation of dendritic cells (DCs) and natural killer cells (NKS), thereby promoting the development of anti-tumor immunity and the establishment of long-term immune memory.
Figure 1Preparation of NP1 and NP2, activation of innate immunity by simultaneous induction of pyroptosis and CGAS-STING signaling pathways, and enhancement of T cell-mediated anti-tumor immunity through the synergistic effect of NP1 and NP2 in a protocol map.
The results show that this nano** system not only provides a light-controllable method to induce pyroptosis and activate the STING pathway, but also enables near-infrared fluorescence bioimaging-guided photoimmunity**. Leveraging the benefits of PDT, near-infrared fluorescence bioimaging, and TME modulation activated via concurrent pyroptosis and CGAS-STING pathways, offers potential progression for photoimmune** cancers.
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