Engineered cyclic peptide targeting ITGA5 disrupts tumor–stroma interaction to overcome desmoplasia and resistance in pancreatic ductal adenocarcinoma

The tumor-stroma interaction contributes to the aggressive and resistance nature of pancreatic ductal adenocarcinoma (PDAC), leading to treatment failure. Cancer-associated fibroblasts (CAFs), a key cell type in the stroma, produce abundant extracellular matrix (ECM) and exhibit crosstalk with cancer cells inducing chemoresistance. In this study, we designed a cyclic peptide (cyAV3.3) targeting integrin <i>α</i>5 (ITGA5) to disrupt CAF-induced desmoplasia and crosstalk with cancer cells. <i>In vitro</i>, cyAV3.3 inhibited the differentiation of pancreatic stellate cells into CAFs and reduced ECM production. In 3D co-cultured human spheroid models, the peptide decreased markers of resistance (ABCG1, BCL2, CXCR4), stemness (WNT1, CD44) and ECM remodeling (COL1A1, MMP2/9, LOX) and enhanced gemcitabine efficacy. <i>In vivo</i>, radiolabeled cyAV3.3 exhibited high tumor accumulation and retention following parenteral injections in a co-injection xenograft tumor model. Intriguingly, combination of cyAV3.3 with gemcitabine resulted in improved therapeutic efficacy of gemcitabine in co-injection xenograft and genetically engineered <i>LSL-Kras</i> ^G12D/+ <i>LSL-Trp53</i> ^R172H/+ <i>Pdx1-Cre</i> (KPC) PDAC models. These effects were attributed to reduced desmoplasia, vasculature compression and enhanced infiltration of cytotoxic T cells and apoptosis. This study presents a novel cyclic peptide inhibiting ITGA5-mediated tumor-stroma interaction and thereby reduce desmoplasia and resistance, ultimately enhancing chemotherapy efficacy in PDAC.