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However, conventional DNA\u2010damaging therapies lack tumor specificity and cause damage to normal tissue. Furthermore, dendritic cells (DCs), central to the STING\u2010mediated immune response, exhibit extrinsic immunosuppression via inhibitory receptors such as T\u2010cell immunoglobulin and mucin\u2010domain containing\u20103 (TIM\u20103), which impairs DNA internalization and subsequent pathway activation. Herein, we engineered a telomere stress\u2010induced nanoreactor composed of a pH\u2010responsive zeolitic imidazolate framework\u20108 encapsulating telomerase\u2010targeted 6\u2010thio\u20102\u2019\u2010deoxyguanosine (6\u2010thio\u2010dG), with TIM\u20103 antibodies (\u03b1TIM\u20103) adsorbed onto its surface. Following accumulation in the tumor, the nanoreactor degrades within the acidic tumor microenvironment, releasing 6\u2010thio\u2010dG to induce tumor cell\u2010specific telomeric DNA damage. Concurrently, the \u03b1TIM\u20103 blocks TIM\u20103 receptors on DCs, thereby enhancing their internalization of the released DNA. This dual\u2010action strategy drives robust cGAS\u2010STING 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\u2010intrinsic telomere stress with DC\u2010extrinsic checkpoint inhibition, this work establishes a precision platform for cGAS\u2010STING pathway activation, presenting a promising therapeutic strategy for telomerase\u2010positive malignancies.<\/jats:p>","DOI":"10.1002\/advs.202518356","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:01:25Z","timestamp":1768975285000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Programmable Nanoreactor Orchestrates Cascade of DNA Sensing to Amplify cGAS\u2010STING Activation for Cancer Immunotherapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Shuang","family":"Liang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing P. R. 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