A Dual STING-activating Nanosystem Expands Cancer Immunotherapeutic Temporal Window

Stimulator of interferon genes (STING) is a promising target against cancer by bridginginnate and adaptive immunity in favor of an immunologically hot tumor milieu. However, the transient nature of immune signal transduction renders small-molecule STING agonists susceptible to short time-effectiveness. Here, we develop a dual-STING-activating micelle system (D-SAM) to dynamically programme STING stimulation kinetics. Mechanistically, the natural STING ligand cGAMP encapsulated in D-SAM promptly initiates STING signaling, while the pH-sensitive polymer PC7A disassembled from the micelle shell buffers lysosomal protons and retards STING degradation. As a result, D-SAM prolongs STING activity and facilitates antigen presentation on dendritic cells as well as extends cytotoxic T lymphocyte primingagainst tumors, with less effector T cell exhaustion or death. In established, metastatic,and recurring murine tumor models, D-SAM significantly improves antitumor efficacyand confers survival benefit than either single agonist, clinically-used Adu-S100, orcGAMP-based delivery preparations. However, activation of the STING pathway may affect the expression of autophagy-related genes, thereby affecting the efficacy of tumour immunotherapy. To investigate the effect of D-SAM on the expression of autophagy-related genes, we conducted this study.