Antigen‐Targeting Inserted Nanomicelles Guide Pre‐Existing Immunity to Kill Head and Neck Cancer

Abstract A significant challenge in cancer therapy is the identification of suitable targets that are specifically and uniformly expressed across heterogeneous tumors. The efficacy of pre‐existing antiviral immunity in tumor treatment is limited by the absence of corresponding targets. This study develops a novel platform of antigen‐targeted inserted nanomicelles, preS1 (an antigen of hepatitis B virus)‐pHLIP nanomicelles, in which tumor‐targeting nanomicelles release antigens that label tumor tissue for pre‐existing immunity‐mediated lysis in situ. In animal models of head and neck cancers, including head and neck squamous cell carcinoma and anaplastic thyroid cancer, preS1‐pHLIP nanomicelles effectively inhibited tumor growth, recurrence, and metastasis in animals pre‐immunized with preS1. This therapeutic effect is associated with an increase in the proportion of preS1‐specific B cells and activated tumor‐specific T cells within the tumor microenvironment. Overall, this work has engineered a nanomicelle that can disguise tumor cells as viruses and achieve tumor killing through the pre‐existing antiviral immune response. This strategy presents a novel approach for treating tumors with ambiguous therapeutic target profiles.