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

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.