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Cascade-activatable small-molecule theranostic nanomicelles for photodynamic-immunotherapy of immune-cold lung tumors
Young-Chan Yoon1, Hyoung-Jun Kim1, Yongdoo Choi1
1Division of Technology Convergence, National Cancer Center, 323 Ilsan-ro, Goyang, Gyeonggi-Do 10408, Republic of Korea.
Abstract:
Lung cancer is the most frequently diagnosed malignancy worldwide and remains the leading cause of cancer-related mortality. Effective treatment of immune-cold lung tumors remains particularly challenging due to poor immune activation and the off-target toxicity of conventional therapies. Here, we present a small-molecule-based self-assembled nanotheranostic micelle (FRANT) that employs cascade activation via folate receptor-mediated endocytosis and subsequent cathepsin B-specific cleavage, enabling tumor-selective near-infrared (NIR) fluorescence imaging and photodynamic therapy (PDT). FRANT maintains a serum-stable quenched state, thereby suppressing background fluorescence and minimizing off-target phototoxicity during systemic circulation. With an optimal hydrodynamic size of 13.7 nm, FRANT achieves deep tumor penetration, precise NIR fluorescence recovery, and robust singlet oxygen generation selectively in cancer cells. Importantly, FRANT-mediated PDT transformed immune-cold lung tumors by inducing immunogenic cell death and synergizing with PD-1 blockade, resulting in enhanced CD8⁺ T cell infiltration and durable tumor regression without systemic toxicity. Collectively, this study introduces a novel class of serum-stable, cascade-activated small-molecule nanotheranostics that couple diagnostic precision with immunomodulatory efficacy, offering a powerful platform for next-generation lung cancer therapy.
Insights
A novel nanotheranostic micelle (FRANT) effectively treats immune-cold lung tumors. It enables precise imaging and photodynamic therapy, transforming tumors and enhancing T cell response for durable regression.
Area of Science:
- Oncology
- Nanomedicine
- Immunotherapy
Background:
- Lung cancer is a leading cause of cancer mortality worldwide.
- Treating immune-cold lung tumors is challenging due to low immune activation and therapy toxicity.
- Novel therapeutic strategies are needed for effective lung cancer treatment.
Purpose of the Study:
- To develop a small-molecule-based nanotheranostic micelle (FRANT) for immune-cold lung tumors.
- To enable tumor-selective near-infrared (NIR) fluorescence imaging and photodynamic therapy (PDT).
- To assess FRANT's ability to transform tumors and synergize with immunotherapy.
Main Methods:
- FRANT utilizes cascade activation via folate receptor-mediated endocytosis and cathepsin B cleavage.
- FRANT exhibits serum stability and a quenched state to minimize off-target effects.
- FRANT's efficacy was evaluated in immune-cold lung tumor models, assessing tumor penetration, imaging, PDT, and immune response.
Main Results:
- FRANT demonstrated deep tumor penetration and selective NIR fluorescence recovery.
- FRANT-mediated PDT induced immunogenic cell death and singlet oxygen generation in cancer cells.
- Combination therapy with FRANT-PDT and PD-1 blockade enhanced CD8+ T cell infiltration and achieved durable tumor regression without systemic toxicity.
Conclusions:
- FRANT is a novel, serum-stable, cascade-activated nanotheranostic for precise lung cancer diagnosis and therapy.
- FRANT-mediated PDT can overcome immune exclusion in lung tumors and synergize with immunotherapy.
- This platform offers a promising approach for next-generation lung cancer treatment with enhanced immunomodulatory efficacy.
