Stimuli-responsive STING nanovaccine for systemic therapy of HPV-induced cancers

In recent years, therapeutic cancer vaccines have been extensively investigated, aiming to boost cancer-specific T cells crucial for antitumor activity. The effectiveness of these vaccines is often limited by insufficient immune activation and suboptimal antigen delivery. Stimulator of interferon genes (STING) is an important immune signaling protein that activates host defense genes against infection and cancer. Clinical evaluation of small-molecule STING agonists has shown tepid antitumor responses with immune-related toxicities, particularly when they are administered systemically. To overcome these limitations, we report a stimuli-responsive STING nanovaccine for treating human papillomavirus (HPV)-induced cancers. The nanovaccine consists of di-amidobenzimidazoles (diABZI) conjugated to a STING-activating polymer, PSC7A, through an azobenzene linker as an adjuvant, and HPV16 E7 protein as an antigen. The nanovaccine is responsive to acidic pH and NAD(P)H quinone oxidoreductase 1 (NQO1), which enhances antitumor immunity with reduced systemic toxicity. Upon intravenous injection, the STING nanovaccine (25 to 30 nm in diameter) achieved efficient codelivery of E7 protein and STING agonists to the myeloid cell populations in the secondary lymphoid organs and tumors. Interestingly, PSC7A uptake induces NQO1 expression in dendritic cells and macrophages for accelerated diABZI cleavage and STING activation. This results in efficient production of E7-specific CD8⁺ T cells and robust antitumor response in late-stage TC-1 and metastatic MLM3 tumor models. This study illustrates a systemic STING nanovaccine design that allowed not only tumor regression but also markedly reduced systemic toxicity for innate activation to achieve cancer-specific T cell immunity.