Engineering the Immune Adaptor Protein STING as a Biologic

Activation of the stimulator of interferon genes (STING) pathway through cyclic dinucleotides (CDNs) has been explored extensively as potent vaccine adjuvants against infectious diseases as well as to increase tumor immunogenicity towards cancer immunotherapy in solid tumors. Over the last decade, a myriad of synthetic vehicles, including liposomes, polymers, and other nanoparticle platforms, have been developed to improve the bioavailability and therapeutic efficacy of STING agonists in preclinical mouse models. However, synthetic materials may suffer from batch-to-batch variations due to complex formulations, and can also elicit side effects. In contrast, protein therapeutics such as recombinant cytokines and antibodies represent a unique therapeutic modality owing to their physical and biochemical homogeneity. In the present work, we have repurposed the immune adaptor STING as a protein-based delivery system that can efficiently encapsulate CDNs in a load-to-go manner. Moreover, through genetic fusion with a protein transduction domain, the recombinant STING can spontaneously penetrate cells to markedly enhance the delivery of CDNs in a mouse vaccination model and a syngeneic mouse melanoma model. Moreover, motivated by recent findings that certain tumor cells can evade immune surveillance via loss of STING expression, we further unveiled that our STING platform can serve as a functional vehicle to restore the STING signaling in a panel of lung and melanoma cell lines with impaired STING expression. Altogether, our STING-based delivery platform may have implications towards targeting STING-silenced tumors as well as augmenting the efficacy of STING-based vaccine adjuvants.