A molecularly defined polymeric platform for environmentally responsive activation of STING to enhance cancer immunotherapy.

The stimulator of interferon genes (STING) pathway is a promising immuno-oncology target. Despite their potential, STING agonists have yielded underwhelming results in clinical trials due to pharmacological barriers that limit their safety and efficacy. Herein, we describe the design and pre-clinical evaluation of a polymeric dimeric amidobenzimidazole (diABZI) STING agonist delivery platform for cancer immunotherapy. Central to our technology is a stimuli-responsive diABZI-functionalized reversible addition-fragmentation chain transfer (RAFT) polymerization chain transfer agent (CTA) that allows well-defined polymer chains to be grown directly from a single STING agonist. Using a biocompatible poly(N,N'-dimethylacrylamide) polymer as a first-generation scaffold and a disulfide as a clinically relevant linker, we demonstrate our platform liberates a potent diABZI analog under reducing conditions to trigger STING-driven inflammatory gene expression in tumors, thereby stimulating antitumor immunity in multiple murine models and synergizing with α-PD-1 immune checkpoint blockade to eliminate tumors. This work therefore establishes a promising delivery platform for microenvironmental regulation of STING activation with promise as an immunotherapy for cancer.