The stimulator of
interferon genes (
STING) pathway plays an important role in the immune surveillance of
cancer and, accordingly, agonists of
STING signaling have recently emerged as promising
therapeutics for remodeling of the immunosuppressive tumor microenvironment (TME) and enhancing response rates to
immune checkpoint inhibitors. 2'3'-cyclic
guanosine monophosphate-
adenosine monophosphate (2'3'-cGAMP) is the endogenous
ligand for
STING, but is rapidly metabolized and poorly membrane permeable, restricting its use to intratumoral administration. Nanoencapsulation has been shown to allow for systemic administration of
cGAMP and other cyclic dinucleotides (CDN), but little is known about how nanocarriers affect important pharmacological properties that impact the efficacy and safety of CDNs. Using
STING-activating nanoparticles (
STING-NPs) - a polymersome platform designed to enhance
cGAMP delivery - we investigate the pharmacokinetic (PK)-pharmacodynamic (PD) relationships that underlie the ability of intravenously (i.v.) administered
STING-NPs to induce
STING activation and inhibit
tumor growth. First, we demonstrate that nanoencapsulation improves the half-life of encapsulated
cGAMP by 40-fold, allowing for sufficient accumulation of
cGAMP in
tumors and activation of the
STING pathway in the TME as assessed by western blot analysis and gene expression profiling. Nanoparticle delivery also changes the biodistribution profile, resulting in increased
cGAMP accumulation and
STING activation in the liver and spleen, which we identify as dose limiting organs. As a consequence of
STING activation in
tumors, i.v. administered
STING-NPs reprogram the TME towards a more immunogenic antitumor milieu, characterized by an influx of >20-fold more CD4+ and CD8+ T-cells. Consequently,
STING-NPs increased response rates to αPD-L1
antibodies, resulting in significant improvements in median survival time in a B16-F10
melanoma model. Additionally, we confirmed
STING-NP monotherapy in an additional
melanoma (YUMM1.7) and breast
adenocarcinoma (E0771) models leading to >50% and 80% reduction in
tumor burden, respectively, and significant increases in median survival time. Collectively, this work provides an examination of the PK-PD relationship governing
STING activation upon systemic delivery using
STING-NPs, providing insight for future optimization for nanoparticle-based
STING agonists and other immunomodulating nanomedicines.