A Dual-Specificity <scp>d</scp>-Peptide Antagonist of MDM2 and MDMX for Antitumor Immunotherapy

Designing metabolically stable peptides to target interactions of the tumor suppressor protein p53 with the two oncogenic proteins MDM2 and MDMX represents an attractive approach to harvesting "high-hanging fruits" often inaccessible to traditional anticancer drug discovery and development efforts. Here, we report the design of a proteolysis-resistant d-dodecapeptide, termed ^DPMI-ω (EFWYVE^<i>p</i>-ClFEKLLR), capable of disrupting the p53-MDM2/MDMX complex by antagonizing MDM2 and MDMX. ^DPMI-ω, upon fabrication on gold nanoparticles, efficiently traversed tumor cells and killed them by reactivating the p53 signaling pathway. Further, ^DPMI-ω inhibited B16 melanoma growth <i>in vivo</i> and, when combined with an anti-PD1 antibody, powerfully augmented the efficacy of immunotherapy by expanding CD3⁺/CD8⁺ cytotoxic T cells and suppressing CD4⁺/CD25⁺ regulatory T cells. Our work validates the design of a therapeutically viable anticancer peptide, showcasing its potential in combination therapy to treat patients with tumors that are otherwise resistant or poorly responsive to antitumor immunotherapy.