Endosomolytic Polymersomes Increase the Activity of Cyclic Dinucleotide STING Agonists to Enhance Cancer Immunotherapy

Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) are a promising class of immunotherapeutic that activate innate immunity to increase tumor immunogenicity. However, the efficacy of CDNs is limited by drug delivery barriers, including poor cellular targeting, rapid clearance, and inefficient transport to the cytosol where STING is localized. Here we describe STING-activating nanoparticles (STING-NPs), rationally designed polymersomes for enhanced cytosolic delivery of the endogenous CDN ligand for STING, 2’3’ cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). STING-NPs increase the biological potency of cGAMP, enhance STING signaling in the tumour microenvironment and sentinel lymph node, and convert immunosuppressive tumours to immunogenic, tumouricidal microenvironments. This leads to enhanced therapeutic efficacy of cGAMP, inhibition of tumour growth, increased rates of long-term survival, improved response to immune checkpoint blockade, and induction of immunological memory that protects against tumour rechallenge. We validate STING-NPs in freshly isolated human melanoma tissue, highlighting their potential to improve clinical outcomes of immunotherapy.