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

## TL;DR

A new nanomaterial activates the immune system to fight cancer by combining light therapy and immune signaling.

## Contribution

A degradable Au-Zn bimetallic STING nanomodulator that coordinates photothermal therapy and immunotherapy via the cancer-immunity cycle.

## Key findings

- GZn NPs degrade in acidic tumor environments and under NIR-II laser, releasing Zn2+ and inducing ROS burst.
- Zn2+ enhances cGAS activity and synergizes with ROS to activate the cGAS-STING pathway.
- The nanomodulator promotes immunogenic cell death and T cell infiltration, leading to long-term anti-tumor immunity.

## Abstract

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 Zn2+ ions that directly enhance cGAS enzymatic activity. Concurrently, Zn2+ 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 Zn2+ 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 Zn2+ 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.Image 1

•GZn NPs represent a dual-responsive Au-Zn bimetallic STING nanomodulator for controlled Zn2+ release.•GZn NPs induce ROS burst via Zn2+ homeostasis disruption and NIR-II photothermal therapy, causing severe oxidative stress.•GZn NPs activate the cGAS-STING pathway through a dual role: Zn2+ 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.

GZn NPs represent a dual-responsive Au-Zn bimetallic STING nanomodulator for controlled Zn2+ release.

GZn NPs induce ROS burst via Zn2+ homeostasis disruption and NIR-II photothermal therapy, causing severe oxidative stress.

GZn NPs activate the cGAS-STING pathway through a dual role: Zn2+ 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.