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

Abstract

ABSTRACT Immunotherapy has revolutionized the landscape of cancer treatment; however, most current strategies target only isolated steps of the cancer‐immunity cycle and therefore struggle to achieve durable clinical success. Central to immune surveillance, the cGAS‐STING 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‐derived double‐stranded DNA (dsDNA). Here, we report a rationally engineered immune nanoenhancer platform–C‐iNE/A, that reprograms approved chemotherapeutics to initiate robust dsDNA‐driven cGAS‐STING 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‐iNE/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‐based immunotherapy and advance the next generation of tumor‐immunomodulatory regimens.