Amanda Haymond

Despite success in the treatment of some blood cancers and melanoma, positive response to immunotherapies remains disappointingly low in the treatment of solid tumors. The context of the molecular crosstalk within the tumor microenvironment can result in dysfunctional immune cell activation, leading to tumor tolerance and progression. Although modulating these protein–protein interactions (PPIs) is vital for appropriate immune cell activation and recognition, targeting nonenzymatic PPIs has proven to be fraught with challenges. To address this, a synthetic, multivalent molecular modality comprised of small interfering peptides precisely hybridized to a semirigid DNA scaffold is introduced. Herein, a prototype of this modality that targets the IL‐33/ST2 signaling axis, which is associated with tumor tolerance and immunotherapy treatment failure is described. Using peptides that mimic the specific high‐energy “hotspot” residues with which the IL‐33/ST2 coreceptor, IL‐1RAcP, interacts with the initial binary complex, this platform is shown to effectively bind IL‐33/ST2 with a K D of 110 n m . Additionally, this molecule effectively abrogates signal transduction in cell models at high nanomolar concentrations and is exquisitely selective for this complex over structurally similar PPIs within the same cytokine superfamily.