The Aging Microenvironment is a Determinant of Immune Exclusion and Metastatic Fate in Pancreatic Cancer

Abstract Aging is a critical yet understudied determinant in pancreatic ductal adenocarcinoma (PDAC) risk and outcomes. Despite a strong epidemiological association with age, conventional PDAC preclinical models fail to capture the histopathological and stromal complexities that emerge in older organisms. Using an age-relevant syngeneic orthotopic model, we demonstrated that organismal aging accelerates PDAC progression and metastasis. Transcriptomic and secretome profiling identified a conserved extracellular matrix gene signature enriched in cancer-associated fibroblasts (CAFs) from aged tumors, consistent with an augmented fibrotic landscape that supports immunosuppression, metastatic tropism, and poor prognosis. Direct testing of the functional impact of stromal aging in heterochronic co-implantation models revealed that revitalizing the aged tumor stroma with young CAFs restores immune infiltration and attenuates metastasis in older hosts. Conversely, aged CAFs, while immunosuppressive, failed to enhance metastasis in young hosts, suggesting that a youthful microenvironment exerts dominant regulatory control over disease progression. These findings demonstrate that stromal age is a critical modulator of both immune exclusion and metastatic behavior in PDAC. Importantly, this work establishes a conceptual framework for understanding how aging shapes the tumor microenvironment in PDAC and opens a fertile avenue of investigation into age-specific stromal regulation. Moreover, these findings raise compelling questions about the underlying molecular mechanisms and lay the foundation for future efforts to therapeutically target stromal aging in PDAC.