Synergistic Remodeling of Tumor Immune Microenvironment via a DNA Nanodevice Integrating STING Activation and Lysosome‐Targeted PD‐L1 Degradation

ABSTRACT The cGAS‐STING pathway is a cornerstone of innate antitumor immunity; however, its therapeutic potential is often limited by the inefficient cytosolic delivery of agonists and the immunosuppressive tumor microenvironment (TME). Here, we report a DNA nanostructure‐based platform that simultaneously induces lysosomal degradation of immune checkpoint protein PD‐L1 and activates the STING pathway. We demonstrate that STING activation further enhances PD‐L1 degradation, resulting in strong synergistic immune activation. In murine models of triple‐negative breast cancer, the DNA nanodevice effectively reprograms the TME by enhancing dendritic cell maturation and CD8 + T cell infiltration, resulting in potent suppression of both primary tumor growth and pulmonary metastases. This study establishes a versatile nanoplatform that bridges targeted protein degradation with STING‐mediated innate immune activation, provides a promise strategy for cancer immunotherapy.