Cascade-activatable small-molecule theranostic nanomicelles for photodynamic-immunotherapy of immune-cold lung tumors.

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.