Mount Sinai Perturb-map study links PAI1/PAI2-driven fibrin niches to pancreatic tumor immune evasion in Nature

{"Researchers applied Perturb-map spatial genomics to heterogeneous pancreatic ductal adenocarcinoma models, tracking gene-edited cell clones and their immune neighborhoods. They identified PAI1 and PAI2 as drivers of extracellular fibrin accumulation that recruits and polarizes suppressive macrophages while reducing nearby CD8+ T-cell activation and infiltration.","Disruption of the PAI-fibrin axis in these models slowed tumor progression and enhanced checkpoint blockade efficacy. The work also offers mechanistic context for the elevated venous thromboembolism rates observed in pancreatic cancer patients, as tumor-derived PAI proteins simultaneously promote clotting and local immune exclusion.","The findings connect to earlier observational data in NEJM showing dense desmoplasia and M2 macrophage dominance as independent predictors of immunotherapy failure. They extend those associations by demonstrating that niche formation is cell-autonomous and spatially restricted rather than uniform across the tumor.","Next steps require validation in patient-derived xenografts and early-phase trials of PAI-targeted agents combined with PD-1 blockade, with endpoints focused on changes in spatial T-cell density rather than bulk response rates."}