A Programmable Nanoreactor Orchestrates Cascade of DNA Sensing to Amplify cGAS‐STING Activation for Cancer Immunotherapy

ABSTRACT The cGAS‐STING pathway, a critical cytosolic DNA‐sensing mechanism in innate immunity, holds significant promise for cancer immunotherapy. However, conventional DNA‐damaging therapies lack tumor specificity and cause damage to normal tissue. Furthermore, dendritic cells (DCs), central to the STING‐mediated immune response, exhibit extrinsic immunosuppression via inhibitory receptors such as T‐cell immunoglobulin and mucin‐domain containing‐3 (TIM‐3), which impairs DNA internalization and subsequent pathway activation. Herein, we engineered a telomere stress‐induced nanoreactor composed of a pH‐responsive zeolitic imidazolate framework‐8 encapsulating telomerase‐targeted 6‐thio‐2’‐deoxyguanosine (6‐thio‐dG), with TIM‐3 antibodies (αTIM‐3) adsorbed onto its surface. Following accumulation in the tumor, the nanoreactor degrades within the acidic tumor microenvironment, releasing 6‐thio‐dG to induce tumor cell‐specific telomeric DNA damage. Concurrently, the αTIM‐3 blocks TIM‐3 receptors on DCs, thereby enhancing their internalization of the released DNA. This dual‐action strategy drives robust cGAS‐STING activation, enhancing type I interferon production and DCs maturation. In murine models of immunogenic and poorly immunogenic tumors, the nanoreactor significantly suppresses tumor growth and prolongs survival. By coupling tumor‐intrinsic telomere stress with DC‐extrinsic checkpoint inhibition, this work establishes a precision platform for cGAS‐STING pathway activation, presenting a promising therapeutic strategy for telomerase‐positive malignancies.