Abstract B076: PD-L1-Targeting Peptide Synergizes Photodynamic Therapy and Immune Checkpoint Blockade for Systemic Antitumor Immunity

Abstract Background: Antibody-based immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but are limited by high cost, poor tumor penetration, and systemic toxicity. Peptide ICIs offer a promising alternative, though often lacking in vivo potency. This study introduces a dual-function heptapeptide, IKCRPCY (IKC), designed to target PD-L1 and augment photodynamic therapy (PDT) to induce both local and systemic antitumor responses [1]. Methods: IKC was identified through cell-based phage display and subsequently evaluated for its ability to bind PD-L1, activate T-cells, and induce immunogenic cell death (in vitro). A chlorin e6-conjugated variant (Ce6-IKC) was developed for tumor-specific reactive oxygen species (ROS) generation. Antitumor efficacy was assessed in unilateral and bilateral CT26 tumor models (in vivo). Molecular docking and dynamics simulations were performed to evaluate peptide-receptor binding stability. Immune responses, including cytokine expression, immune infiltration, and abscopal effects, were analyzed using ELISA, immunohistochemistry, and flow cytometry [1]. Results: IKC demonstrated nanomolar affinity for PD-L1 and successfully restored IL-2 secretion in co-cultured T cells. Ce6-IKC showed superior tumor selectivity and phototoxicity compared to free Ce6. The combination of IKC and Ce6-IKC PDT significantly suppressed tumor growth, induced immunogenic cell death markers (Calreticulin, HMGB1), and increased CD8+ T-cell infiltration. Notably, this combined therapy reduced contralateral tumor burden by 72%, indicating a robust abscopal effect. Molecular dynamics simulations confirmed that the IKC–PD-L1 complex exhibited stability comparable to therapeutic antibodies, despite IKC's minimalist structure [1]. Conclusions: IKC represents a novel and scalable peptide platform that effectively combines checkpoint blockade with localized photodynamic therapy. Its dual functionality in targeting PD-L1 and enhancing PDT, coupled with its ability to activate systemic immune responses and induce abscopal effects, offers a compelling strategy to overcome the current limitations associated with traditional antibody-based ICIs [1]. Citation Format: Jae Myung Park, Seul Ki Yun, Seon Ju Lee, Moon Hwa Kwak. PD-L1-Targeting Peptide Synergizes Photodynamic Therapy and Immune Checkpoint Blockade for Systemic Antitumor Immunity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B076.