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Near Infrared Photoimmunotherapy for Mouse Models of Pleural Dissemination
Published on: February 9, 2021
Near-Infrared II Photoactivatable Prodrug Enables Tumor-Specific Stimulator of Interferon Genes Activation for
Chunlin Ren1,2,3, Jie Yang4,5,6, Yu Tian4,5,6
1Department of Radiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
Abstract:
The stimulator of interferon genes (STING) pathway is a promising target for cancer immunotherapy, but systemic activation often induces severe toxicity and cytokine storms. To overcome this challenge, we developed a near-infrared II (NIR-II) photoactivatable prodrug, HTAM, for targeted STING activation in the "cold" tumor microenvironment of triple-negative breast cancer. HTAM integrates a mitochondria-targeted photosensitizer (HD) with the STING agonist MSA-2 via a reactive oxygen species (ROS)-cleavable thioacetal-diol linker, enabling efficient tumor targeting and accumulation. Upon 808 nm laser irradiation, HD-generated ROS trigger linker cleavage and spatiotemporally controlled MSA-2 release at the tumor site, thereby activating the STING pathway while minimizing off-target effects. Concurrently, the photodynamic therapy induces DNA damage and immunogenic cell death, amplifying STING signaling and type I interferon production. This synergistic strategy promotes dendritic cell maturation, enhances cytotoxic T lymphocyte infiltration, and effectively reprograms the immunosuppressive microenvironment in the aggressive 4T1 model.
Insights
Researchers developed a novel photoactivatable prodrug for targeted STING pathway activation in triple-negative breast cancer. This approach minimizes toxicity and enhances anti-tumor immunity by combining photodynamic therapy with STING agonism.
Area of Science:
- Biomedical Engineering
- Cancer Immunotherapy
- Drug Delivery Systems
Background:
- The stimulator of interferon genes (STING) pathway is a key target for cancer immunotherapy.
- Systemic STING activation can cause severe toxicity and cytokine storms.
- Triple-negative breast cancer often presents a "cold" tumor microenvironment, limiting immunotherapy efficacy.
Purpose of the Study:
- To develop a targeted STING activation strategy for "cold" tumors.
- To overcome the toxicity associated with systemic STING activation.
- To enhance anti-tumor immune responses in triple-negative breast cancer.
Main Methods:
- Development of a near-infrared II (NIR-II) photoactivatable prodrug (HTAM).
- HTAM integrates a mitochondria-targeted photosensitizer (HD) and STING agonist (MSA-2) via a ROS-cleavable linker.
- NIR-II laser irradiation triggers localized ROS generation, linker cleavage, and controlled drug release.
Main Results:
- HTAM enables spatiotemporally controlled STING activation at the tumor site.
- Photodynamic therapy induces DNA damage and immunogenic cell death, amplifying STING signaling.
- The synergistic approach enhances dendritic cell maturation and cytotoxic T lymphocyte infiltration, reprogramming the tumor microenvironment.
Conclusions:
- This novel prodrug strategy effectively targets and activates the STING pathway in "cold" tumors.
- The combination of photodynamic therapy and STING agonism overcomes systemic toxicity and enhances anti-tumor immunity.
- This approach shows promise for treating aggressive cancers like triple-negative breast cancer.
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