The success of systemic immunotherapy for metastatic cancer depends on the ability to achieve tumor-specific immune activation in normal tissues. The single gate stimulation response system is unable to fully distinguish tumor and normal tissue signals. This study reports an AND gate-controlled nanoparticle, which requires acidic pH and hypoxic signals to activate the interferon-gene-stimulating factor (STING) pathway in the systemic treatment of metastatic cancer. This dual-stimulation-response nanoparticle is formed by combining a small molecule STING agonist with an oxygen-sensitive linker and a pH-sensitive polymer. Biochemical analysis confirmed the pH-hypoxia and logical truth table in STING activation. The nanoparticle agonist significantly reduced the metastatic burden in various immune cold tumor models while showing minimal systemic toxicity. Mechanism studies revealed that STING activation in tumor-resident type I dendritic cells drives the initiation and infiltration of CD8+ T cells and cooperates with immune checkpoint inhibitors. This AND logic nanoparticle platform provides a safe and effective treatment for metastatic cancer mediated by STING immunotherapy. This research was published in Nature Nanotechnology under the title "AND logic nanoparticle for precise immunotherapy of metastatic cancers".
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DOI: 10.1038/s41565-026-02130-3