A stromal PAI1-tPA axis orchestrates immunosuppression in pancreatic cancer.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a dense desmoplastic stroma and an immunosuppressive tumor microenvironment that contribute to therapeutic resistance. Here, we identify plasminogen activator inhibitor 1 (PAI1) as a stroma-derived mediator of immune evasion and tumor progression in PDAC. PAI1 is predominantly produced and secreted by cancer-associated fibroblasts, and its genetic ablation in the stromal compartment impairs tumor growth. Mechanistically, hypoxia induces PAI1 expression in fibroblasts, which in turn shifts macrophages toward immunosuppressive phenotypes and suppresses CD8⁺ T cell infiltration and function. We further show that tissue plasminogen activator (tPA), a direct PAI1 target, is also secreted by fibroblasts and supports antitumor CD8⁺ T cell responses. Notably, elimination of stromal tPA promotes immunosuppressive macrophage phenotypes, reduces CD8⁺ T cell infiltration, and accelerates PDAC progression. These findings define a previously unrecognized PAI1-tPA regulatory axis within the tumor stroma that modulates antitumor immunity. Targeting this pathway may provide a therapeutic opportunity to overcome stroma-driven immune suppression in PDAC.