Second Near-Infrared Light-Activatable Polymeric Nanoantagonist for Photothermal Immunometabolic Cancer Therapy
Cheng Xu1, Yuyan Jiang1, Jingsheng Huang1
1School of Chemical and Biomedical Engineering, Nanyang Technological University, 70 Nanyang Drive, Singapore, 637457, Singapore.
Abstract:
Immunometabolic modulation offers new opportunities to treat cancers as it is highly associated with cancer progression and immunosuppressive microenvironment. However, traditional regimens using nonselective small-molecule immunomodulators lead to the off-target adverse effects and insufficient therapeutic outcomes. Herein a second near-infrared (NIR-II) photothermally activatable semiconducting polymeric nanoantagonist (ASPA) for synergistic photothermal immunometabolic therapy of cancer is reported. ASPA backbone is obtained by conjugating vipadenant, an antagonist to adenosine A2A receptor, onto NIR-II light-absorbing semiconducting polymer via an azo-based thermolabile linker. Under deep-penetrating NIR-II photoirradiation, ASPA induces tumor thermal ablation and subsequently immunogenic cell death, triggers the cleavage of thermolabile linker, and releases the antagonist to block the immunosuppressive adenosinergic pathway. Such a remotely controlled immunometabolic regulation potentiates cytotoxic T cell functions while suppresses regulatory T cell activities, leading to efficient primary tumor inhibition, pulmonary metastasis prevention, and long-term immunological memory. Thereby, this work provides a generic polymeric approach for precise spatiotemporal regulation of cancer immunometabolism.
Insights
This study introduces a novel semiconducting polymer nanoantagonist (ASPA) that uses near-infrared light to treat cancer. ASPA synergistically combines photothermal therapy with immunometabolic modulation, enhancing anti-tumor immune responses and reducing side effects.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Cancer progression is linked to immunometabolic dysregulation and immunosuppressive microenvironments.
- Conventional immunomodulators cause off-target effects and limited efficacy.
Purpose of the Study:
- To develop a novel semiconducting polymeric nanoantagonist (ASPA) for synergistic photothermal immunometabolic cancer therapy.
- To achieve precise spatiotemporal regulation of cancer immunometabolism using NIR-II light activation.
Main Methods:
- Conjugating vipadenant (adenosine A2A receptor antagonist) onto a NIR-II absorbing semiconducting polymer via a thermolabile linker.
- Utilizing second near-infrared (NIR-II) photoirradiation for photothermal ablation and controlled drug release.
- Evaluating the immunometabolic modulation, anti-tumor efficacy, and immunological memory in preclinical models.
Main Results:
- ASPA demonstrated effective tumor thermal ablation and induced immunogenic cell death upon NIR-II irradiation.
- Cleavage of the thermolabile linker released vipadenant, blocking the immunosuppressive adenosinergic pathway.
- Enhanced cytotoxic T cell activity, suppressed regulatory T cell function, leading to primary tumor inhibition and metastasis prevention.
Conclusions:
- The developed ASPA provides a versatile platform for targeted cancer immunometabolic therapy.
- This approach enables precise control over the tumor microenvironment, potentiating anti-tumor immunity.
- The study highlights a promising strategy for overcoming limitations of traditional cancer immunotherapies.
