AlbiCDN： Albumin-binding Amphiphilic STING Agonists Augments the Immune Activity for Cancer Immunotherapy

Abstract

Stimulator of interferon genes (STING) has been an attractive target in cancer immunother-apy. However, natural ligands cyclic dinucleotides (CDNs) and CDN derivatives have demonstrated limited efficacy in clinical trials. This limitation stems from the inherent structure of CDNs, which leads to enzymatic degradation, poor cell internalisation, rapid clearance from the tumour microenvironment, and dose-limiting toxicity. In this study, we developed an amphipathic STING agonist, termed albu-min-binding CDNs (AlbiCDN), to enhance the efficacy of c-di-GMP (CDG) via a lipid-conjugated strategy. The Lipid provided a platform for albu-min hitchhiking, which facilitated the cytoplasmic delivery of CDG without the use of any exogenous components. In addition, incorporating a stimuli-responsive lipid motif further enhanced the cellular release of CDG. Our results indicated that CDG-1C14, an AlbiCDN, efficiently stimulated the maturation and activation of antigen-presenting cells through STING activation. Furthermore, CDG-1C14 exhibited a significant inhibitory effect on the tumour therapeutic model. Therefore, AlbiCDN is a potent platform for cancer immunotherapy that can expedite clinical translation.