PDAC forms a dense, T-cell-excluded tumor microenvironment, but the molecular drivers of this niche remain unclear. Using Perturb-map, a spatial functional genomics platform, we identify the fibrinolysis regulators Serpinb2 (PAI-2) and Serpine1 (PAI-1) as key mediators of immune evasion. Tumor-derived SERPINs stabilize a fibrin-rich ECM that anchors macrophages, promotes immunosuppressive polarization, and excludes cytotoxic T cells. Their deletion suppresses tumor growth and sensitizes PDAC to anti-PD-1 therapy.