Heparanase blockade sensitizes pancreatic ductal adenocarcinoma cells to chemotherapy and unleashes antitumor immunity

Desmoplasia, a dense fibrotic reaction, is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and fuels chemoresistance through multiple mechanisms. Here, we evaluated heparanase (HPSE), an endoglycosidase that remodels extracellular matrix (ECM) and drives fibrogenesis, as a potential target in PDAC. Immunohistochemical analysis of human PDAC tissues showed elevated HPSE expression, along with increased levels of fibroblast growth factors 1 and 2 (FGF1/2), reflecting their liberation by HPSE-catalyzed heparan sulfate cleavage. High expression of all three proteins was associated with worse overall and disease-free survival. In vitro coculture assays showed that the HPSE inhibitor PI-88 suppressed PDAC cell-induced activation of pancreatic stellate cells (PSCs) and prevented ECM stiffening without inducing cytotoxicity. Mechanistically, tumor-derived HPSE activated ERK signaling and promoted FGF1/2 production in PSCs, both of which were effectively suppressed by PI-88. In orthotopic mouse models, gemcitabine treatment upregulated HPSE and FGF1/2, whereas gemcitabine-resistant tumors exhibited further increases in these factors, accompanied by enhanced PSC activation and collagen deposition. Importantly, triple therapy with PI-88, gemcitabine, and Abraxane significantly suppressed tumor growth and prolonged survival relative to all mono- and doublet regimens. Immune profiling revealed that this combination reduced PSC activation, contracted M2 macrophage and regulatory T cell populations, and expanded M1 macrophages, CD8⁺ T cells, and NK cells. In conclusion, these data underscore HPSE as a key driver of fibrosis and chemoresistance in PDAC and support HPSE inhibition as a promising strategy to enhance therapeutic efficacy.