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.