Dumbbell-shape DNA structure activates cGAS-STING pathway for enhanced checkpoint immunotherapy in colorectal cancer.

Colorectal cancer (CRC), a prevalent malignancy of the digestive tract with poor responsiveness to existing immunotherapies, presents an urgent need for strategies to overcome therapeutic resistance. The cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) pathway, a key mediator of innate antitumor immunity through DNA sensing and type I interferon (IFN-I) signaling, offers a promising target for intervention. However, conventional STING agonists are limited by insufficient tumor targeting and systemic adverse effects. To address these challenges, this study developed a tumor-specific, dumbbell-shaped DNA structure (DDS) engineered for precise activation of the cGAS-STING pathway. Simultaneously, DDS enhanced the efficacy of checkpoint immunotherapy in CRC. Experimental validation demonstrated that DDS orchestrates dendritic cell maturation and cytotoxic T lymphocyte priming via STING-dependent immune signaling while synergizing with anti-programmed cell death protein 1 (PD-1) therapy to reverse immunosuppressive tumor microenvironmental constraints. By integrating spatially controlled STING activation with checkpoint blockade, this nucleic acid-based platform overcomes critical delivery barriers of traditional agonists and establishes a novel paradigm for enhancing immunotherapy efficacy in CRC.