When defense turns dangerous: The dual nature of senescence in pancreatic ductal adenocarcinoma

Cellular senescence has emerged as a context-dependent determinant of pancreatic ductal adenocarcinoma (PDAC) progression and therapeutic response. In early pancreatic tumorigenesis, oncogene-induced senescence acts as a robust tumor-suppressive mechanism that limits KRAS-driven malignant transformation. However, this protective barrier is progressively circumvented during disease evolution. In established PDAC, senescence acquires predominantly pro-tumorigenic functions, particularly within the stromal compartment. Senescent cancer-associated fibroblasts reshape the tumor microenvironment through the senescence-associated secretory phenotype (SASP), fostering desmoplasia, immune evasion, and resistance to therapy. In parallel, conventional chemotherapy and targeted treatments induce therapy-induced senescence in tumor cells, contributing to tumor persistence and relapse. Recent advances in senescence-associated gene signatures and SASP profiling have enabled the stratification of PDAC patients according to prognosis and immune landscape. This review critically discusses the dual roles of senescence in PDAC and evaluates emerging senescence-targeted therapeutic strategies, including senolytic and senomorphic approaches, as promising avenues to improve treatment efficacy.