Abstract 2701: iRGD peptide therapy transforms immunosuppressive microenvironment to immune-favorable state in pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits a complex, immunosuppressive tumor immune microenvironment (TIME), necessitating molecular-level understanding to identify therapeutic targets. We investigated how iRGD peptide therapy remodels the immunosuppressive TIME to an immune-favorable state using single-cell spatial molecular analysis. Methods: Single-cell level in situ molecular imaging was performed using Xenium analyzer with 5K gene panel on tumor samples from humanized PDAC mice (n=7) treated with iRGD monotherapy (n=3) or control (n=4), enabling comprehensive spatial molecular characterization of the TIME. Results: iRGD therapy significantly transformed the immunosuppressive TIME to an immune-favorable state through T-cell composition remodeling. We observed increased populations of CD4+ memory T cells, CD4+ helper T cells, and cytokine-secreting effector T cells, indicating enhanced immune memory and effector functions. Concurrent decreases in regulatory T cells and activated CD4+ T cells reflected reduced immune suppression. Additionally, decreased TGF-β signaling in the iRGD cohort suggested TGF-β antagonism as a mechanism for overcoming immunosuppression. Conclusions: iRGD therapy effectively converted the immunosuppressive PDAC microenvironment to an immune-favorable state by enhancing beneficial T cell populations and reducing immunosuppression through TGF-β pathway modulation. These findings support previous work by Kuroda et al. and provide mechanistic rationale for the ongoing iRGD-based immunotherapy clinical trial (iLSTA:ACTRN12623000223639).Acknowledgments: We thank DeepL for the English language editing. Citation Format: Minji Kim, Yoon Ho Choi, Hotaka Kawai, Yukihito Kuroda, Norio Miyamura, Kazuki N. Sugahara, Tae Hyun Hwang. iRGD peptide therapy transforms immunosuppressive microenvironment to immune-favorable state in pancreatic ductal adenocarcinoma [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 2701.