Homeostasis is the fundamental premise of health, which is kept by systemic regulation of nerve-endocrine-immune axis. Previously, we have defined cancer is a systematic disease which is characterized by abnormal cell growth in a defined tissue or organ under progressive systemic dysregulation of nerve-endocrine-immune axis (Primary Liver Cancer, Springer 2012). Serotonin (5-HT) is a well-known neuroendocrine factor. We demonstrated that local 5-HT in pancreatic ductal adenocarcinoma (PDAC) microenvironment facilitated the formation of HTR2B/Lyn/P85 complex and further activates PI3K/Akt/mTOR signaling, which ultimately increases the protein level of c-Myc and HIF1a and enhances Warburg effect via regulating glycolytic enzymes. The majority of 5-HT in the periphery is synthesized and released from enterochromaffin cells and it enters the blood stream where it is transported into platelets and stored. Platelet infiltration was significantly elevated in pancreatic cancer and was inversely correlated with patient outcome. 5-HT was imported into macrophage and modulated macrophage polarization and metabolism properties via serotonylation (a novel posttranslational modification) in PDAC microenvironment. Together, serotonin receptors could be promising therapeutic targets for PDAC.