Sono‐Driven STING Activation using Semiconducting Polymeric Nanoagonists for Precision Sono‐Immunotherapy of Head and Neck Squamous Cell Carcinoma

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.