Discovery of molecular glues for modulating MHC presentation of cancer neoantigens

Antigen presentation by MHC class I molecules is essential for cancer immunosurveillance, but many cancer-specific antigens fail to form complexes with Class I MHC and are poorly presented on the cell surface. In this study, we present a chemical strategy to overcome this limitation by identifying peptide MHC glues (PMGs) that promote the formation of peptide-MHC complexes with otherwise unpresentable cancer antigens. Crystal structures of these complexes show that our compounds stabilize antigen-MHC binding by making simultaneous interactions with the MHC protein and the antigen peptides. These findings reveal a new approach for chemically rewiring Class I MHC antigen presentation and accessing rare cancer antigens for therapeutic targeting.