A dual-STING-activating nanosystem expands cancer immunotherapeutic temporal window

作者：Jian Wang, Xiaohu Wang, Qingqing Xiong, Shan Gao, Shihao Wang, Siqi Zhu, Shuting Xiang, Mingxi Li, Haitang Xie, Suxin Li · 发表于：Cell Reports Medicine · 年份：2024 · DOI：10.1016/j.xcrm.2024.101797 · 被引用次数：23 · 研究领域：interferon and immune responses、Viral Infections and Vectors、Viral Infections and Outbreaks Research

Stimulator of interferon genes (STING) is a promising antitumor target via bridging innate and adaptive immunity, yet the transient nature of immune signal transduction renders small-molecule agonists susceptible to short time effectiveness. Here, we report a dual-STING-activating micelle system (D-SAM) to dynamically program STING kinetics. Mechanistically, the natural ligand cGAMP encapsulated in D-SAM initiates STING signaling, while the pH-sensitive polymeric agonist PC7A disassembled from micelle shell buffers lysosomal protons and retards STING degradation. This prolonged STING activity facilitates dendritic cell (DC) antigen presentation and extends cytotoxic T lymphocyte priming. D-SAM improves efficacy over single soluble or delivered agonists against established, metastatic, and recurring murine tumors. Specific depletion of STING in DCs or blockade of CD8 + T cell infiltration abrogates therapeutic effects. The feasibility of immune modulation is further validated in resected human patient tissues. This work underscores the temporal rhythm of STING as crucial for mounting a potent and enduring antitumor immune response. • Small-molecule STING agonist (cGAMP) exhibits transient immune activity • PC7A polymer prevents STING degradation through lysosomal buffering • PC7A and cGAMP assemble into a nanoparticle (D-SAM) with prolonged STING activation • D-SAM facilitates DC antigen presentation and extends CD8 + T priming against cancer Wang et al. develop a dual-STING-a...