Degradable STING nanomodulators orchestrate the innate-to-adaptive immune response for NIR-II photothermal-immunotherapy via a cancer-immunity cycle

Activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has become a valuable approach for enhancing the efficacy of immunotherapeutic treatments. Here, a degradable Au-Zn bimetallic STING nanomodulator (designated as GZn NPs) was constructed to coordinate the second near-infrared window (NIR-II) photothermal therapy and immunotherapy. Under acidic tumor microenvironment conditions, plus with NIR-II laser irradiation, GZn NPs undergo responsive degradation, releasing Zn 2+ ions that directly enhance cGAS enzymatic activity. Concurrently, Zn 2+ overload triggers excessive reactive oxygen species (ROS) generation, which, together with the photothermal effect of gold nanostars, produces a synergistic ROS burst. The resulting oxidative stress intensively damages mitochondria and the nucleus, promoting the accumulation of cytosolic dsDNA, thereby synergistically with Zn 2+ activating the cGAS-STING signals. NIR-II photothermal therapy and ROS-mediated oxidative stress induce immunogenic cell death (ICD), which, combined with cGAS-STING pathway activation, promotes dendritic cells (DCs) maturation and T cell infiltration for primary tumor regression. This process also establishes long-term anti-tumor immunity to inhibit tumor recurrence, orchestrating the cycle from innate to adaptive immunity. Collectively, this study presents a promising STING nanomodulator that demonstrates the potential of NIR-II photothermal-immunotherapy in cancer treatment. This work presents a degradable Au-Zn bimetallic STING nanomodulator (GZn NPs). The construct degrades under acidic tumor microenvironment and NIR-II laser irradiation, causing Zn 2+ release and a synergistic ROS burst. This dual outcome activates the cGAS-STING pathway and induces immunogenic cell death, which initiates an amplifying cancer-immunity cycle and ultimately achieves robust antitumor immunity and long-term immune memory. • GZn NPs represent a dual-responsive Au-Zn bimetallic STING nanomodulator for controlled Zn 2+ release. • GZn NPs induce ROS burst via Zn 2+ homeostasis disruption and NIR-II photothermal therapy, causing severe oxidative stress. • GZn NPs activate the cGAS-STING pathway through a dual role: Zn 2+ potentiates cGAS enzymatic activity while synergizing with oxidative stress-induced dsDNA. • GZn NPs activate the cGAS-STING pathway and immunogenic cell death, promoting T cell infiltration and immune memory. • GZn NPs orchestrate the innate-to-adaptive immune response, establish a cancer-immunity cycle.