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

Therapeutic resistance in PDAC is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer associated fibroblasts (CAFs). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAFs) in mouse and human PDAC. These SenCAFs are a subset of myofibroblastic CAFs that localize near tumors ducts, have distinct phenotypes and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we employed a LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Senescence depletion with the KPPC-IA model or with the senolytic drug ABT263/Navitoclax, delayed tumor progression, reduced fibrosis, and relieved immune suppression in macrophages and T lymphocytes. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Examination of the tumor microenvironment with depletion of senescent fibroblasts in PDAC