Simultaneous Activation of Pyroptosis and cGAS‐STING Pathway with Epigenetic/ Photodynamic Nanotheranostic for Enhanced Tumor Photoimmunotherapy

作者：Feixiang Ding, Junyan Liu, Kelong Ai, C. F. Xu, Xiao‐Yuan Mao, Zhaoqian Liu, Haihua Xiao · 发表于：Advanced Materials · 年份：2023 · DOI：10.1002/adma.202306419 · 被引用次数：102 · 研究领域：interferon and immune responses、Inflammasome and immune disorders、Immune Response and Inflammation

Promoting innate immunity through pyroptosis induction or the cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway activation has emerged as a potent approach to counteract the immunosuppressive tumor microenvironment and elicit systemic antitumor immunity. However, current pyroptosis inducers and STING agonists often suffer from limitations including instability, unpredictable side effects, or inadequate intracellular expression of gasdermin and STING. Here, a tumor-specific nanotheranostic platform that combines photodynamic therapy (PDT) with epigenetic therapy to simultaneously activate pyroptosis and the cGAS-STING pathway in a light-controlled manner is constructed. This approach involves the development of oxidation-sensitive nanoparticles (NP1) loaded with the photosensitizer TBE, along with decitabine nanomicelles (NP2). NP2 enables the restoration of STING and gasdermin E (GSDME) expression, while NP1-mediated PDT facilitates the release of DNA fragments from damaged mitochondria to potentiate the cGAS-STING pathway, and promotes the activation of caspase-3 to cleave the upregulated GSDME into pore-forming GSDME-N terminal. Subsequently, the released inflammatory cytokines facilitate the maturation of antigen-presentation cells, triggering T cell-mediated antitumor immunity. Overall, this study presents an elaborate strategy for simultaneous photoactivation of pyroptosis and the cGAS-STING pathway, enabling targeted photoimmunotherapy in immuno...