Citation: Zhiyu Zhang, Wenfei Xu, Zhitong Chen, Xiran He, Xujuan Li, Zishan Huang, Hong Sun, Zhaogang Sun, Hongqian Chu, Wenjing Liu. Dual-stimuli responsive nanoagonist activating the STING and TLR9 pathways for enhanced immunotherapy[J]. Chinese Chemical Letters, ;2026, 37(11): 112911. doi: 10.1016/j.cclet.2026.112911 shu

Dual-stimuli responsive nanoagonist activating the STING and TLR9 pathways for enhanced immunotherapy

Zhiyu Zhang ^{a, 1} ,
Wenfei Xu ^{a, 1} ,
Zhitong Chen ^a ,
Xiran He ^b ,
Xujuan Li ^c ,
Zishan Huang ^a ,
Hong Sun ^a ,
Zhaogang Sun ^{a, *,} ,
Hongqian Chu ^{a, *,} ,
Wenjing Liu ^{a, *,}

a.
Translational Medicine Center, Beijing Tuberculosis and Thoracic Tumor Research Institute / Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
b.
Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute / Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
c.
Yun’an District Traditional Chinese Medicine Hospital, Yunfu 527500, China

sunzg75@163.com

chq0314@bjmu.edu.cn

liuwenjing@ustc.edu

Received Date: 13 March 2026
Revised Date: 8 May 2026
Accepted Date: 9 May 2026
Available Online: 10 May 2026

Figures(6)

Despite the tremendous progress that immunotherapy has made from a marginal concept to a first-line treatment for cancer, the effective activation of innate immunity remains a challenge. The foremost strategy for effective immune activation focuses on harnessing the adaptive immune response. Currently, stimulator of interferon genes (STING) and Toll-like receptor 9 (TLR9) have emerged as particularly promising targets for bridging innate and adaptive immunity. However, single-agonist therapies targeting TLR9 and STING are inadequate for immune activation due to their limited function and susceptibility to the compensatory mechanisms of the tumor microenvironment (TME), and are accompanied by off-target effects, which limit their wide clinical application. Here, we demonstrate a dual-stimuli-responsive nanoagonist named ZIF@AC by integration of acid-degradable zeolitic imidazolate framework-8 (ZIF-8) and adenosine 5′-triphosphate (ATP)-activatable CpG oligonucleotides (ODNs) for TLR9 and STING co-activation. We found that ZIF@AC not only exhibited a favorable safety profile but also effectively reversed immunosuppression within the TME. This reversal was achieved by increasing the M1-type macrophage ratio, promoting dendritic cell (DC) maturation, and enhancing the secretion of pro-inflammatory factors. Consequently, these changes led to an increase in the infiltration of effector T cells and potentiated the antitumor immune response in vivo, and ultimately resulted in effective tumor suppression. This nanoagonist represents a pivotal advance toward optimally safe and potent cancer immunotherapies.
- Nanoagonist,
- Immunotherapy,
- Tumor microenvironment,
- Toll-like receptor 9 (TLR9),
- Stimulator of interferon genes (STING),
- Metal-organic framework (MOF)
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