Tumor-Oriented Delivery of a Dimeric STING Agonist Using an H-Ferritin Nanocage Widens the Therapeutic Window for Cancer Immunotherapy

The cGAS-STING signaling pathway is a pivotal regulator of both innate and adaptive immunity, driving production of type I interferon and recruitment of immune cells, with important therapeutic potential in oncology. However, the therapeutic potential of STING agonists is currently hampered by systemic toxicity and poor tumor selectivity. Here, we report a tumor-oriented nanocarrier (HFn@diBSP01) constructed by encapsulating the dimeric STING agonist diBSP01 within human H-ferritin nanocages. This formulation achieves pH-triggered release, minimizing premature leakage while enabling an improved intracellular delivery in the acidic tumor microenvironment. Compared with free diBSP01, HFn@diBSP01 markedly improves systemic tolerability and sustains potent antitumor efficacy across multiple murine models. Mechanistically, HFn@diBSP01 potentiates STING signaling to orchestrate DC maturation and CD8 + T-cell recruitment, thereby effectively remodeling the tumor immune microenvironment. Our findings further demonstrate ferritin nanocages as a versatile delivery platform that enhances the safety and efficacy profiles of systemic STING agonists, expanding their potential in cancer immunotherapy.