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Central to immune surveillance, the cGAS\u2010STING pathway orchestrates innate and adaptive responses by promoting dendritic cell maturation, cytotoxic T lymphocyte infiltration, and durable immunological memory. However, chemotherapeutic activation of this axis remains elusive due to a paucity of safe, efficacious, and translatable inducers of tumor\u2010derived double\u2010stranded DNA (dsDNA). Here, we report a rationally engineered immune nanoenhancer platform\u2013C\u2010iNE\/A, that reprograms approved chemotherapeutics to initiate robust dsDNA\u2010driven cGAS\u2010STING activation in tumors even at low drug doses. Guided by machine learning, we optimize chemotherapeutic encapsulation and combine it with photophysically triggered mild hyperthermia to impair DNA repair while sparing healthy tissues. This cascade promotes intratumoral dsDNA accumulation, immunogenic release, and sustained immune activation. C\u2010iNE\/A elicited potent immune responses across tumor models, enhancing dendritic cell maturation, amplifying cytotoxic T lymphocyte infiltration, suppressing metastasis, and establishing memory T cell populations. Our approach establishes a generalizable strategy to convert conventional chemotherapeutics into immune activators at safe drug doses, offering a clinically relevant platform to overcome current limitations in STING\u2010based immunotherapy and advance the next generation of tumor\u2010immunomodulatory regimens.<\/jats:p>","DOI":"10.1002\/adma.202516524","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T15:20:03Z","timestamp":1766589603000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["An Immune Nanoenhancer Revitalizes Chemotherapeutics to Tailor Tumor\u2010Derived dsDNA for Anticancer Immunoengineering"],"prefix":"10.1002","volume":"38","author":[{"given":"Yiming","family":"Liu","sequence":"first","affiliation":[{"name":"Peptide Biomedicine Laboratory (PBL) College of Biology Hunan University  Changsha Hunan 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