AND logic nanoparticle for precision immunotherapy of metastatic cancers

Success in systemic immunotherapy against metastatic cancer hinges on the ability to achieve tumour-specific immune activation over normal tissues. Single-gate stimuli-responsive systems are not adequate at differentiating tumour versus normal tissue signals. Here we report an AND-gated nanoparticle that requires acidic pH and hypoxia signals to activate the stimulator of interferon genes (STING) pathway in systemic therapy of metastatic cancers. The dual stimuli-responsive nanoparticle consists of a small-molecule STING agonist conjugated to a pH-sensitive polymer through a hypoxia-sensitive linker. Biochemical analyses confirmed the (pH-hypoxia) AND logic truth table in STING activation. The nanoparticle agonist significantly reduced metastatic burdens in multiple immune-cold tumour models while exhibiting minimal systemic toxicity. Mechanistic investigation revealed that STING activation in tumour-resident type I dendritic cells drives CD8⁺ T cell priming and infiltration, which synergizes with immune checkpoint inhibitors. This AND logic nanoplatform offers a safe and efficacious therapeutic for STING-mediated immunotherapy against metastatic cancers.