Zinc cyclic di-AMP nanoparticles target and suppress tumours via endothelial STING activation and tumour-associated macrophage reinvigoration
Menée à l'aide de lignées cellulaires et de modèles de tumeurs pancréatiques et de gliomes, cette étude met en évidence les effets antitumoraux et le mécanisme d'action de nanoparticules sphériques comportant des dimères d'adénosines monophosphates cycliques liées à du zinc
The clinical utility of stimulator of interferon genes (STING) agonists has been limited due to poor tumour-targeting and unwanted toxicity following systemic delivery. Here we describe a robust tumour-targeted STING agonist, ZnCDA, formed by the encapsulation of bacterial-derived cyclic dimeric adenosine monophosphate (CDA) in nanoscale coordination polymers. Intravenously injected ZnCDA prolongs CDA circulation and efficiently targets tumours, mediating robust anti-tumour effects in a diverse set of preclinical cancer models at a single dose. Our findings reveal that ZnCDA enhances tumour accumulation by disrupting endothelial cells in the tumour vasculature. ZnCDA preferentially targets tumour-associated macrophages to modulate antigen processing and presentation and subsequent priming of an anti-tumour T-cell response. ZnCDA reinvigorates the anti-tumour activity of both radiotherapy and immune checkpoint inhibitors in immunologically ‘cold’ pancreatic and glioma tumour models, offering a promising combination strategy for the treatment of intractable human cancers.