TME/NIR Dual-Responsive Zinc-Based Targeted Nanoagonist for Multimodal Amplification of STING-Mediated Cancer Immunotherapy

  • Adv Sci (Weinh). 2026 Jun 9:e23182. doi: 10.1002/advs.202523182.
Kepeng Hu  1  2  3 ,  Jiawei Wang  1  2  3 ,  Wei Zhang  1  2  3 ,  Zhixuan Wu  1  2  3 ,  Jing Chen  1  2  3  4 ,  Yujing He  1  2  3 ,  Xiyue Duan  5 ,  Yaoting He  5 ,  Xin Xin  5 ,  Haoyi Xiang  1  2  3 ,  Yijing Wang  1  3  4 ,  Chengwei Wu  5 ,  Yang Yi  5 ,  Qing Meng  1  2  3 ,  Yuqian Qiao  6 ,  Kui Cheng  5 ,  Xiaojun Long  1  2  3 ,  Zhangfa Song  1  2  3  4
Affiliations
  • 1. Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 2. Zhejiang Key Laboratory of Biological Treatment, Hangzhou, Zhejiang, China.
  • 3. Key Laboratory of Integrated Traditional Chinese and Western Medicine Research on Anorectal Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 4. School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 5. School of Materials Science and Engineering, State Key Laboratory of Silicon and Advanced Semiconductor Materials, Zhejiang University, Hangzhou, Zhejiang, China.
  • 6. School of Materials Science and Engineering, Nankai University, Tianjin, China.
PMID: 42261811 DOI: 10.1002/advs.202523182
Abstract

The precise activation of the cGAS-STING pathway for effective tumor immunotherapy remains a significant challenge due to the complexity of immune responses and tumor microenvironment (TME) limitations. Here, a multifunctional nanoagonist, cRGD-PDA/ZIF8@ICG/TPT (cDZ@IP), was developed to realize nano-metabolite-driven multimodal synergistic activation of the STING pathway and enhanced immune recognition. The agonist combines cRGD peptide-targeted polydopamine-coated zeolitic imidazolate framework-8 with the Photosensitizer indocyanine green and the chemotherapeutic drug topotecan. Upon near-infrared laser irradiation, cDZ@IP degrades within the TME, generating high levels of Reactive Oxygen Species, inducing mitochondrial stress, and releasing endogenous mitochondrial DNA. Additionally, topotecan enhances DNA damage accumulation by inhibiting nuclear DNA repair. Zn2 + released from the agonist further amplifies cGAS-STING pathway activation, thereby ensuring a robust immune response. The mild photothermal therapy-induced immunogenic cell death promotes the initiation of antitumor immunity, while also enhancing the effectiveness of immune checkpoint blockade. In vivo studies show that cDZ@IP significantly inhibits primary and distant tumor growth and prevents lung metastasis, providing a promising strategy for STING pathway-targeted Cancer Immunotherapy.

Keywords
cGAS‐STING pathway; cancer immunotherapy; immunogenic cell death; nano‐metabolite; tumor microenvironment response.
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