Peptide-Polyanion conjugate to Activate STING Innate Immune Signaling

Technology

First, therapeutic peptides derived from the C-terminal tail of STING for the recruitment of TBK1 and IRF3 are synthesized with an N-terminal azido-lysine handle for click chemistry conjugation to a polyanion backbone, such as poly(L-glutamate), with a pre-specified percentage of reactive alkyne side chains. After conjugation, backbone displays multiple TBK1 and IRF3 recruitment peptides at a tunable ratio, allowing the relative density of each peptide type to be optimized independently. The strong negative charge of the polyanion backbone allows for efficient encapsulation and intracellular delivery using polymer or lipid nanoparticles or other vehicles designed for negatively charged cargo. Once delivered to the cytosol, the peptide-polyanion conjugate mimics the high-valency display of protein-protein interaction motifs found in activated multimeric signaling complexes, scaffolding the cytosolic interaction of TBK1 and IRF3 to drive downstream innate immune signaling. This produces a transcriptional response similar to that of a conventional STING agonist, even in tumor cells with deficient STING expression, and results in the polarization of tumor cells and surrounding immune cells toward an inflammatory, anti-tumor state that can slow tumor growth and improve response to other immunotherapies such as checkpoint blockade.

Problem Addressed

STING is a promising cancer immunotherapy target; however, STING agonists have shown modest clinical efficacy because STING expression is frequently lost in cancer cells through mechanisms such as epigenetic silencing or upstream signaling disruption, rendering the downstream pathway unreachable. Epigenetic strategies to restore STING expression before agonist treatment are complex and require two sequential treatments, complicating clinical use. Existing STING-mimicking therapeutics, such as cytosolic delivery of a truncated STING protein, have shown some pre-clinical potency, but are limited by the difficulty of efficiently delivering large protein fragments cytosolically and their failure to adequately activate downstream signaling proteins TBK1 and IRF3 in some cell types. The present technology overcomes these challenges by directly engaging TBK1 and IRF3, while its nucleic-acid-like charge enables efficient cytosolic delivery using standard polymer or lipid nanoparticle systems.

Advantages

• Overcomes STING deficiency in cancer cells: The conjugate acts directly on intact downstream targets, enabling innate immune activation independent of STING expression. In vitro, the conjugate induced cytokine secretion in STING-deficient ovarian cancer cells that showed no response to the clinical STING agonist ADU-S100.
• On-target activation mirroring conventional STING agonism: The conjugate induced a transcriptional response highly correlated with the clinical STING agonist ADU-S100, supporting specific, on-target innate immune activation without major off-target signaling.
• Compatible with a broad range of existing intracellular delivery vehicles: The polyanionic backbone enabled cytosolic delivery across all six tested vehicles, including three LNP formulations and three polymer-based systems, without requiring bespoke carrier development.
• In vivo proof of concept in a clinically challenging cancer indication: In two independent mouse models of metastatic ovarian cancer, a disease with over 70% STING loss and poor response to existing immunotherapies, conjugate-loaded LNPs elevated inflammatory cytokine levels, repolarized the tumor microenvironment, and extended survival.
• Versatile platform with broad applicability beyond STING: The peptide-polyanion conjugate architecture is generalizable to any short linear protein-protein interaction motif, with potential to modulate a wide range of cytosolic signaling pathways inaccessible to small molecules or biologics.

Publications

Kaskow, Justin A., Julia Treese, Anita Gaenko, et al. “A Multivalent Peptide-Polymer Conjugate Material Mimics STING to Therapeutically Activate Innate Immune Signaling.” bioRxiv, March 26, 2026.