The induction of type I interferon (IFN) via the stimulator of IFN genes (STING) pathway constitutes a highly important part of immune responses against various cancers and infections. Consequently, the administration of STING agonists such as cyclic dinucleotides (CDNs) has been identified as a promising approach to target these diseases. In cancer cells, STING signaling is frequently impaired by epigenetic silencing of STING; hence, conventional delivery of only its agonist CDN may be insufficient to trigger STING signaling. In this invention, while expression of a STING protein lacking the transmembrane (TM) domain is known to be unresponsive to STING agonists and is dominant-negative when coexpressed with the full-length STING inside cells, it has been observed that the recombinant STING protein lacking TM could effectively trigger STING signaling when delivered in vitro and in vivo, including in STING-deficient and defective cell lines. Thus, this bio-inspired method using TM-deficient STING may present a new and universally applicable platform for CDN delivery.
Technology Overview
Northeastern researchers propose an idea to develop a preassembled CDN-STING complex in the form of a ribonucleoprotein (RNP) to address the STING problems by utilizing RNPs to improve the efficacy of mRNA delivery and RNA interference. In nature, the STING protein forms a dimer to sandwich one CDN ligand with a nanomolar (nM) dissociation constant, which suggests a strong interaction that can achieve great RNP stability from both formulation and delivery perspectives. The STING protein can be genetically fused with a cell-penetrating peptide and/or tumor-specific peptide to simultaneously serve as a carrier for CDNs and as a functional complex to activate STING signaling in DCs and the TME. Alternatively, the RNP can be encapsulated by existing delivery platforms that have been developed for protein delivery.
Current efforts to increase the bioavailability of CDNs in the TME cannot fully activate STING signaling in tumors when there is low or lack of expression of the CDN receptor STING. 
For instance, in lung and gastric cancers, low STING expression correlates with cancer progression and poor prognosis. Moreover, ~19% of the population exhibits nonsynonymous mutations in STING and is insensitive to natural CDNs. Additionally, since CDNs must form a bound complex with STING protein inside cells to activate its downstream signaling, codelivery of preassembled CDN/STING complexes can circumvent the requirement for preexisting STING expression.
Can provide a new mode of delivery for STING agonists to greatly enhance therapeutic efficacy by activating STING signaling in multiple cancer types. In addition to acting as a monotherapy, the delivery of RNPs consisting of STING and CDNs can be integrated with existing immunotherapy approaches including combination with immune checkpoint inhibitors to mitigate their resistance in a majority of cancer patients, and co-administration with tumor neoantigens to enhance personalized cancer vaccines.
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Colin Sullivan
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Northeastern University
Jiahe Li