Engineering the Immune Adaptor Protein STING as a Functional Carrier

Abstract

AbstractActivation of the stimulator of interferon genes (STING) pathway through cyclic dinucleotides (CDNs) is being explored as potent vaccine adjuvants against infectious diseases and to increase tumor immunogenicity toward cancer immunotherapy. To date, 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. Compared to synthetic materials, protein‐based carriers represent an attractive delivery platform owing to their biocompatibility, amenability to genetic engineering, and intrinsic capacity to form well‐defined structures. Here, the immune adaptor STING is engineered as aprotein‐based delivery system for efficient encapsulation and intracellular delivery of CDNs. 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 melanoma model. As certain tumor cells can evade immune surveillance via loss of STING expression, authors further unveiled that the STING platform can serve as a functional vehicle to restore the STING signaling in cell lines with impaired STING expression. Altogether, their delivery platform may offer a unique direction toward targeting STING‐silenced tumors and augmenting the efficacy of STING‐based vaccine adjuvants.