Abstract 3216: A dual-acting chimeric peptide inhibits tumor growth by inhibiting PD-L1 and inducing immunogenic cell death

Abstract Blockade of the immune checkpoint proteins such as PD-L1 enables to overcome the resistance of cancer cells against the immune surveillance. Nevertheless, the blockade therapy itself lacks cytotoxic killing ability to cancer cells. In this study, we exploited PD-L1-targeted cytotoxic peptides that block PD-L1 on the surface of tumor cells and induce the tumor cell death as well. As targeting peptides, we used PD-L1Pep-1 and PD-L1Pep-2 that bind to and block PD-L1. As a cytotoxic peptide, the KLAKLAKKLAKLAK peptide (named K) was fused to the targeting peptide. PD-L1Pep-1-K and PD-L1Pep-2-K decreased cell survival in PD-L1-expressing tumor cells. Both peptides were internalized into tumor cells through the receptor-mediated endocytosis and localized at lysosomes and also at mitochondria. The peptide-induced cell death was accompanied by an increase in the exposure of CRT on the cell surface and extracellular release of ATP and HMGB1, which are markers of immunogenic cell death (ICD). PD-L1Pep-2-K rekindled the T-cell activity including proliferation and cytokine secretion when co-cultured with tumor cells. Systemic administration of PD-L1Pep-2-K inhibited tumor growth more efficiently than PD-L1Pep2 and anti-PD-L1 antibody. These results suggest that the PD-L1-targeted cytotoxic peptide is a novel dual-acting therapeutic agent capable of PD-L1 blocking and ICD induction for cancer immunotherapy. Citation Format: So-Young Park, Smriti Gurung, Byungheon Lee. A dual-acting chimeric peptide inhibits tumor growth by inhibiting PD-L1 and inducing immunogenic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3216.