Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer.

PDAC therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with anabundance of cancer associated fibroblasts (CAFs). Distinct CAF populations were recently identified, but thephenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify asubpopulation of senescent myofibroblastic CAFs (SenCAFs) in mouse and human PDAC. These SenCAFs area phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate withPDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we employed a LSLKRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with induciblesenescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC modelsrelieved immune suppression by macrophages, delayed tumor progression and increased responsiveness tochemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immunecell dysfunction.