Restoring Cell–Cell Communication to Elicit Bystander Effect Using a DNA‐Based Nanocomplex for Robust Immunotherapy

Abstract The activation of the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway has shown promise in enhancing antitumor immunity. However, the pathway involved de novo transcription and translation processes, which delays immune responses. Besides, the rapid clearance of the secondary messenger cyclic GMP‐AMP (cGAMP) by extracellular hydrolase limits its availability, attenuating STING signaling and resulting in insufficient therapeutic efficacy. Herein, we constructed a DNA‐based nanocomplex, which could restore cell‐cell communication to elicit bystander effect for enhancing cGAS‐STING responses. By virtue of its capabilities to promote gap junctional intercellular communication for cGAMP transfer and to trigger immunogenic cell death (ICD) of tumor cells through bioorthogonal reaction‐catalyzed drug synthesis, the cGAS‐STING pathway in tumor cells was activated and amplified in a transcription‐independent, horizontal manner. The nanocomplex presented safe and robust antitumor effects against not only primary tumors but also distant and metastatic tumors via abscopal effects. The work highlighted the effects of restoring cell–cell communication on cGAS‐STING activation and provided a new perspective for antitumor immunotherapy.