Intervention in the Crosstalk between the cGAS-STING Pathway and Autophagy Using an Oligonucleotide-Based Bioorthogonal Platform for Amplifying Immunotherapy

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) pathway can respond to double-stranded DNA (dsDNA) to mediate innate immunity. However, activation of the cGAS/STING pathway initiates autophagy, which typically plays a negative regulatory role in the cGAS-STING pathway, largely attenuating the efficacy of antitumor immunity. Herein, we construct an oligonucleotide-based bioorthogonal platform to intervene in the crosstalk between the cGAS-STING pathway and autophagy, thereby achieving enhanced immunotherapy. In the platform, a dsDNA segment conjugated with unpaired guanosines serves as an agonist for the cGAS-STING pathway. The i-motif acts as a template for synthesizing palladium nanoparticles, which catalyze the synthesis of autophagy inhibitor and also function as carriers of oligonucleotides. Furthermore, the platform includes an aptamer for targeted delivery to cancer cells. In cancer cells, the platform activates the cGAS-STING pathway and disrupts autophagy, enhancing the anticancer immunity. This study provides a promising strategy to improve outcomes in tumor immunotherapy.