Multivalent Peptide-Guided EZH2 Degradation Sensitizes Immune Checkpoint Therapy in TNBC.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Although an immune checkpoint blockade can reduce metastasis, its effectiveness is hindered by the immunosuppressive microenvironment in TNBC. EZH2 is overexpressed in TNBC, and patients with high EZH2 expression are associated with poor prognoses. The study developed EIP103 as a first-in-class peptide degrader that targets EZH2 through multivalent, high-affinity interactions and induces conformational destabilization, representing a mechanism distinct from that of the small molecule inhibitor EPZ-6438. The results demonstrated that EIP103 induces immunogenic cell death through lipid peroxidation, resulting in enhanced immune cell infiltration. Additionally, molecular dynamics (MD) simulations and biochemical assays revealed that the peptide EIP103 binds to the SET domain of EZH2, altering its structure and triggering proteasomal degradation via Praja Ring Finger Ubiquitin Ligase 2 (PJA2)-mediated ubiquitination. Harboring both enzymatic inhibition and post-translational regulation properties, EIP103 exerts durable efficacy and activates antitumor immunity, making it a promising therapeutic candidate for TNBC.