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

Despite prolific advances in cancer immunotherapy, such as immune checkpoint blockade (ICB), many patients do not achieve complete tumor remission. Insufficient antitumor responses have spurred efforts to invoke complementary elements of the immune system, including the stimulator of interferon genes (STING) pathway. 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. To address these challenges, we report the development of a biodegradable, highly potent STING agonist in conjugate nanoparticle formulation for systemic delivery of sub-microgram doses of STING agonists. Here, we show, in multiple models of murine cancer, that the intravenous administration 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 ICB led to largely curative outcomes, even after tumor re-challenge, in mouse models of melanoma and colon cancer. 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.