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

• Published in: Cell reports. Medicine p. 101797
• Main Authors: Wang, Jian, Wang, Xiaohu, Xiong, Qingqing, Gao, Shan, Wang, Shihao, Zhu, Siqi, Xiang, Shuting, Li, Mingxi, Xie, Haitang, Li, Suxin
• Format: Journal Article
• Language: English
• Published: United States 17.10.2024
• Subjects: dual-activation; STING; nanoparticle; temporal window; cancer immunotherapy
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101797

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.