Pancreatic cancer cachexia: A systemic consequence of multi-organ interactions

Pancreatic cancer cachexia is a complex, multifactorial syndrome characterized by progressive wasting of skeletal muscle and adipose tissue, contributing to poor prognosis and high mortality in pancreatic cancer patients. While muscle and fat loss are the hallmark features, pancreatic cancer cachexia is increasingly recognized as a systemic disorder involving extensive metabolic and inflammatory disruptions across multiple organs. Tumor-derived cachexia-inducing factors play a central role in driving systemic inflammation, metabolic dysregulation, and neuroendocrine abnormalities, leading to anorexia, gut dysbiosis, cardiac dysfunction, and pancreatic exocrine and endocrine insufficiency. These multi-organ disturbances form a vicious cycle that accelerates disease progression and complicates clinical management. In this review, we provide a comprehensive overview of pancreatic cancer cachexia, including its definitions, classification, and heterogeneous clinical presentations. We further examine recent findings on the molecular mediators of cachexia and their role in inter-organ communication networks. Additionally, we highlight advances in experimental models that enable the dissection of pancreatic cancer cachexia pathophysiology, and discuss emerging mechanism-based therapeutic strategies aimed at disrupting the cachexia cycle. A deeper understanding of the systemic nature of pancreatic cancer cachexia and the crosstalk among affected organs may inform the development of multi-targeted interventions and hold promise for improving patient outcomes.