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Sono-Driven STING Activation using Semiconducting Polymeric Nanoagonists for Precision Sono-Immunotherapy of Head and
Jianli Jiang1, Miaomiao Zhang2, Tao Lyu1
1College of Chemistry & Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China.
Abstract:
Immunotherapy has offered new opportunities to treat head and neck squamous cell carcinoma (HNSCC); however, its clinical applications are hindered by modest therapeutic outcomes and the "always-on" pharmacological activity of immunomodulatory agents. Strategies for precise spatiotemporal activation of antitumor immunity can tackle these issues but remain challenging. Herein, a semiconducting polymeric nanoagonist (SPNM) with in situ sono-activatable immunotherapeutic effects for precision sono-immunotherapy of HNSCC is reported. SPNM is self-assembled from a sonodynamic semiconducting polymer core conjugated with a stimulator of interferon genes (STING) agonist (MSA-2) via a singlet oxygen cleavable linker. Under sono-irradiation, SPNM produces singlet oxygen not only to eradicate tumor cells to trigger immunogenic cell death but also to unleash caged STING agonists via the cleavage of diphenoxyethene bonds for in situ activation of the STING pathway in the tumor region. Such sono-driven STING activation mediated by SPNM promotes effector T cell infiltration and potentiates systemic antitumor immunity, eventually leading to tumor growth inhibition and long-term immunological memory. This study thus presents a promising strategy for the precise spatiotemporal activation of cancer immunotherapy.
Insights
This study introduces a novel semiconducting polymeric nanoagonist for head and neck cancer immunotherapy. Ultrasound activates this nanoagonist to precisely target tumors, enhancing immune response and inhibiting cancer growth.
Area of Science:
- Biomedical Engineering
- Cancer Immunology
- Nanotechnology
Background:
- Immunotherapy shows promise for head and neck squamous cell carcinoma (HNSCC) but faces challenges with limited efficacy and continuous drug activity.
- Precise spatiotemporal control over antitumor immunity activation is crucial for improving therapeutic outcomes.
Purpose of the Study:
- To develop a novel semiconducting polymeric nanoagonist (SPNM) for precise, ultrasound-triggered immunotherapy of HNSCC.
- To investigate the sono-activatable release of a STING agonist for localized immune activation within the tumor microenvironment.
Main Methods:
- SPNM self-assembly from a sonodynamic semiconducting polymer core and a STING agonist (MSA-2) linked by a singlet oxygen-cleavable bond.
- In situ sono-irradiation to induce singlet oxygen production and cleavage of the linker, releasing the STING agonist.
- Evaluation of immunogenic cell death, STING pathway activation, T cell infiltration, and systemic antitumor immunity.
Main Results:
- Sono-irradiation of SPNM generated singlet oxygen, leading to tumor cell eradication and immunogenic cell death.
- In situ cleavage of the linker released the STING agonist, activating the STING pathway specifically in the tumor region.
- SPNM treatment promoted effector T cell infiltration, enhanced systemic antitumor immunity, inhibited tumor growth, and established long-term immunological memory.
Conclusions:
- SPNM offers a precise spatiotemporal strategy for activating cancer immunotherapy via ultrasound.
- This sono-activatable approach overcomes limitations of traditional immunotherapies, showing potential for HNSCC treatment.
