Conjugated STING-agonist nanoparticles enhance antitumor immunity in multiple tumor models

Abstract Stimulator of interferon genes (STING) agonist is a promising activator of antitumor immunity. However, the systemic delivery of STING agonist, based on cyclic dinucleotides (CDNs), yields limited anticancer activity owing to poor serum stability and cellular internalization. Here, we show, in multiple models of murine cancer, that the intravenous administration of sub-microgram doses of chemically-modified CDNs covalently bound to poly(β-amino ester) nanoparticles (CDN-NP) results in potent innate and adaptive antitumor immune responses. The combination of CDN-NPs and immune checkpoint blockade led to largely curative outcomes, even after tumor re-challenge, in mouse models of melanoma and colon cancer and to survival benefit in a preclinical murine breast cancer model. The NPs activated STING signaling in immune cells in tumor and lymphoid tissues. We demonstrate, in a mouse melanoma model, that cancer-cell STING signaling is not necessary for therapeutic responses, but act as a nanoparticle reservoir, releasing CDN to proximal immune cells.