# A Programmable Nanoreactor Orchestrates Cascade of DNA Sensing to Amplify cGAS‐STING Activation for Cancer Immunotherapy

## TL;DR

A nanoreactor was developed to activate the cGAS-STING pathway in cancer cells, improving immunotherapy by targeting DNA damage and boosting immune response.

## Contribution

A novel nanoreactor that combines telomere stress and checkpoint inhibition to enhance cGAS-STING activation in cancer immunotherapy.

## Key findings

- The nanoreactor induces tumor-specific DNA damage and enhances dendritic cell activation.
- The treatment significantly suppresses tumor growth and prolongs survival in murine models.
- The strategy activates the cGAS-STING pathway, promoting type I interferon production and immune cell maturation.

## Abstract

The cGAS‐STING pathway, a critical cytosolic DNA‐sensing mechanism in innate immunity, holds significant promise for cancer immunotherapy. However, conventional DNA‐damaging therapies lack tumor specificity and cause damage to normal tissue. Furthermore, dendritic cells (DCs), central to the STING‐mediated immune response, exhibit extrinsic immunosuppression via inhibitory receptors such as T‐cell immunoglobulin and mucin‐domain containing‐3 (TIM‐3), which impairs DNA internalization and subsequent pathway activation. Herein, we engineered a telomere stress‐induced nanoreactor composed of a pH‐responsive zeolitic imidazolate framework‐8 encapsulating telomerase‐targeted 6‐thio‐2’‐deoxyguanosine (6‐thio‐dG), with TIM‐3 antibodies (αTIM‐3) adsorbed onto its surface. Following accumulation in the tumor, the nanoreactor degrades within the acidic tumor microenvironment, releasing 6‐thio‐dG to induce tumor cell‐specific telomeric DNA damage. Concurrently, the αTIM‐3 blocks TIM‐3 receptors on DCs, thereby enhancing their internalization of the released DNA. This dual‐action strategy drives robust cGAS‐STING activation, enhancing type I interferon production and DCs maturation. In murine models of immunogenic and poorly immunogenic tumors, the nanoreactor significantly suppresses tumor growth and prolongs survival. By coupling tumor‐intrinsic telomere stress with DC‐extrinsic checkpoint inhibition, this work establishes a precision platform for cGAS‐STING pathway activation, presenting a promising therapeutic strategy for telomerase‐positive malignancies.

A programmable nanoreactor was engineered for precise cGAS‐STING pathway activation in cancer immunotherapy. This strategy bridges targeted tumor DNA damage with DC immunomodulation, providing a translatable platform to unlock innate and adaptive antitumor immunity.