Abstract 2906: The iRGD peptide reprograms the tumor microenvironment and potentiates immunotherapy in an advanced humanized PDAC mouse model

Abstract Pancreatic ductal adenocarcinoma (PDAC) presents a desmoplastic, poorly perfused, and immunosuppressive tumor microenvironment (TME) that limits immunotherapy. We recently discovered that the tumor-penetrating peptide iRGD, which binds αv integrins and neuropilin-1 (NRP-1), reprograms this hostile TME by targeting tumor-infiltrating regulatory T cells (Tregs) and inhibiting transforming growth factor-β (TGF-β), a key driver of fibrosis, vascular collapse, and immune suppression. Here, we show that iRGD elicits similar effects in humanized PDAC mice reconstituted with functional human immune cells. PDAC-infiltrating Tregs expressed αvβ5 integrin in addition to NRP-1, enabling iRGD-mediated targeting and depletion in transgenic and syngeneic PDAC models. In contrast, splenic Tregs lacked αvβ5 and remained unaffected. αvβ5+ Tregs represented a highly suppressive CCR8+ Treg subset. These αvβ5+ Tregs were also identified in human PDAC tissue and could be induced from human CD4+ T cells. Beyond Tregs, αvβ5 was broadly expressed on cancer cells, fibroblasts, and endothelial cells in PDAC. Our recent studies showed that the αvβ5-rich TME facilitates integrin-dependent TGF-β activation, which is effectively antagonized by iRGD. Owing to its tumor-penetrating activity, systemic iRGD monotherapy broadly inhibited TGF-β signaling in syngeneic PDAC tumors, improving vascular perfusion, reducing stromal fiber density, and enabling deep infiltration of CD8+ T cells. iRGD also significantly enhanced the response to immune checkpoint blockade. In humanized PDAC mice, iRGD reproduced these TME-modifying effects: it reduced vascular collapse and hypoxia, increased pericyte coverage, decreased stromal fibers, improved the CD8/Treg ratio, and activated human cytotoxic T cells. Early data further suggest that combining iRGD with checkpoint blockade prolongs survival in these mice. These findings indicate that the biological activity of iRGD is preserved across species despite potential differences in its target proteins. Collectively, iRGD orchestrates a coordinated reprogramming of the PDAC TME through αvβ5-dependent Treg targeting and TGF-β suppression, resulting in enhanced anti-tumor immunity in both mouse and humanized models. These results strongly support further clinical development of iRGD-based immunotherapies and highlight αvβ5 as a promising, mechanistically defined target for treating PDAC and other desmoplastic, TGF-β-rich tumors. Citation Format: Norio Miyamura, Yukihito Kuroda, Kodai Suzuki, Yuki Kunisada, Hotaka Kawai, Henri Havia, Tero Järvinen, Moriya Tsuji, Kazuki N. Sugahara. The iRGD peptide reprograms the tumor microenvironment and potentiates immunotherapy in an advanced humanized PDAC mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2906.