A PAI-macrophage axis in pancreatic cancer heterogeneity and immune evasion

Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, ECM-rich microenvironment, yet tumors display striking heterogeneity. This raises the question of whether immune resistance is a global tumor property or organized within spatially restricted niches. Using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This revealed early gene-driven remodeling of local immune neighborhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (PAI1) and SERPINB2 (PAI2) as dominant regulators of tumor microenvironment control and immune evasion. These SERPINs promote stabilization of fibrin-rich ECM niches that spatially retain and program macrophages toward immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacologic inhibition of PAI1 or CD18, improves tumor control and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumors revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+MARCO+ macrophages. These findings identify cancer-derived SERPINE1/B2 as local spatial organizers of immune suppression, linking tumor-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.