A dual-STING-activating nanosystem expands cancer immunotherapeutic temporal window
Jian Wang, Xiaohu Wang, Qingqing Xiong, Shan Gao, Shihao Wang, Siqi Zhu, Shuting Xiang, Mingxi Li, Haitang Xie, Suxin Li
Abstract
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-activating micelle system (D-SAM) to dynamically program STING kinetics in dendritic cells, leading to enhanced antigen presentation and prolonged cytotoxic T lymphocyte response against cancer. D-SAM improves safety and efficacy in established, metastatic, and recurring murine tumor models.