Integrin α5β1 in pancreatic ductal adenocarcinoma: Tumour‒stroma crosstalk, hypoxia and therapeutic targeting.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is characterised by aggressive biological behaviour, marked therapeutic resistance and a dense desmoplastic tumour microenvironment. Integrin α5β1, the principal fibronectin receptor, has emerged as an important mediator of tumour-stroma interactions through its roles in cell adhesion, mechanotransduction, migration, survival and extracellular matrix (ECM) remodelling. MAIN BODY: Increasing evidence indicates that integrin alpha 5 (ITGA5)/integrin α5β1 is upregulated in PDAC cells and stromal compartments and is associated with invasion, fibrosis, therapeutic resistance and poor prognosis. Hypoxia, a defining feature of PDAC, may further enhance α5β1-related signalling by promoting stromal activation and ECM remodelling. This review summarises the structural and signalling features of integrin α5β1, its role in hypoxia-related interactions between tumour cells and the stroma, its contribution to therapeutic resistance in PDAC, and current therapeutic strategies targeting this integrin. CONCLUSION: Integrin α5β1 is a biologically relevant therapeutic target for modulating the fibrotic stroma and overcoming treatment resistance in PDAC, and it may also be implicated in tumorstroma crosstalk within the hypoxic microenvironment. Successful clinical translation of α5β1-targeted strategies will likely require further mechanistic investigation, biomarker-guided patient selection, and rational combination approaches to address pathway redundancy and the limited efficacy of monotherapy.