Zinc-c-di-AMP nanoparticles target and suppress tumors via endothelial STING activation and tumor associated macrophage reinvigoration

Abstract Mounting evidence indicates that the stimulator of interferon genes (STING) pathway is critical for the effectiveness of standard cancer treatments. However, systemic delivery of STING agonists remains a challenge due to poor tumor-targeting and unwanted toxicities. Here we describe a robust tumor-targeted STING agonist, ZnCDA, formed by the encapsulation of bacterial-derived cyclic dimeric adenosine monophosphate (CDA) in nanoscale coordination polymers. Intravenously injected ZnCDA prolonged CDA circulation and efficiently targeted tumors, mediating robust antitumor effects in a diverse set of preclinical cancer models. Moreover, endothelial STING activation promotes the accumulation of ZnCDA in the tumor tissues by amplifying the enhanced permeability and retention (EPR) effect. In this study, we discover that type I IFN is not required for the antitumor effects of STING agonism by ZnCDA, indicating that differentially formulated STING activators may suppress tumor growth in different ways. Using metal- or dye-labelled nanoparticles, we identified a group of tumor-associated macrophages (TAMs) as the cellular target of ZnCDA in the tumor immune microenvironment. RNA-seq analysis indicated the modulation of TAMs for antigen processing and presentation via STING activation. We further showed that TAMs with ZnCDA uptake promoted an antitumor T cell response. Lastly, we utilized two immunologically “cold” tumor models, a fragment Panc02-SIY pancreatic cancer model and an intracranial GL261 glioma model, both of which represent intractable fatal human cancers, to provide a proof-of-concept strategy for combining ZnCDA with immune checkpoint blockade or radiotherapy in aggressive, difficult-to-treat tumors. a grant from the Ludwig Foundation and an NIH grant (R01CA262508) to R.R.W., NIH grants (R01CA223184 and R01CA216436) to W.L. and NIH grants (R35CA232109 and R01AI141333) to J.P.Y.T. A.P. is the recipient of a Walter Benjamin scholarship provided by the German Research Foundation (Deutsche Forschungsgemeinschaft). J.B. was supported by a Clinical Therapeutics Training Grant (T32GM007019).