Immunotherapy has completely changed the landscape of cancer treatment; however, most current strategies target only isolated steps in the cancer immunity cycle, making it difficult to achieve lasting clinical success. As the core of immune surveillance, the cGAS-STING pathway coordinates innate and adaptive responses by promoting dendritic cell maturation, cytotoxic T lymphocyte infiltration, and durable immune memory. However, due to the lack of safe, effective, and translatable tumor-derived double-stranded DNA (dsDNA) inducers,and durable immune memory, coordinating innate and adaptive responses. However, due to the lack of safe, effective, and translatable tumor-derived double-stranded DNA (dsDNA) inducers, chemotherapy-driven activation of this axis remains difficult to achieve. This paper reports a rationally engineered immune nano-enhancer platform, C-iNE/A, which reprograms approved chemotherapeutic drugs to trigger robust dsDNA-driven cGAS-STING activation in tumors, even at low drug doses. Guided by machine learning, we optimized the chemotherapy packaging,And combined with mild hyperthermia triggered by photophysics to inhibit DNA repair while protecting healthy tissues. This cascade reaction promotes the accumulation of dsDNA within tumors, immunogenic release, and sustained immune activation. C-iNE/A induces a strong immune response in tumor models, promotes dendritic cell maturation, and enhances cytotoxic T lymphocyte infiltration.Inhibit metastasis and establish memory T cell populations. Our approach establishes a translatable strategy to convert conventional chemotherapeutic drugs into safe-dose immune activators, providing a clinically relevant platform to overcome the limitations of existing STING-based immunotherapies and to advance next-generation tumor immune modulation strategies.

Original link

An Immune Nanoenhancer Revitalizes Chemotherapeutics to Tailor Tumor-Derived dsDNA for Anticancer Immunoengineering

Pub Date : 2025-12-24

DOI: 10.1002/adma.202516524

Yiming Liu,  Yachao Li,  Wensheng Gong,  Dongzhe Zou,  Beiling Guo,  Zenan Zeng,  Xiaoxiao Li,  Yini Xu,  Xianghui Xu