How the diffuse neuroendocrine system shapes health, homeostasis, and cancer

The diffuse neuroendocrine system (DNES) consists of dispersed neuroendocrine (NE) cells that bridge nervous, immune, and endocrine pathways across organs. Evolutionarily, DNES traces to primitive metazoans where single cells combined neural and immune roles, later diversifying into specialized vertebrate NE cells. Hallmark traits include dense-core granules, amine metabolism, “salt-and-pepper” chromatin, and regulation by ASCL1, NEUROG3, and INSM1. Remarkable plasticity allows immune and epithelial cells to acquire NE features under stress, while carcinomas exploit this program to form aggressive neuroendocrine tumors (NETs) and resist therapy. Canonical neuroimmune circuits, the Vagus-driven inflammatory reflex and hypothalamic–pituitary–adrenal stress axis, illustrate DNES coordination of systemic responses. Clinically, DNES-derived neoplasms span multiple organs, produce diverse hormonal syndromes, and are managed with somatostatin analogues, epigenetic drugs, and emerging immunotherapies. Recognizing DNES as a diffuse, integrative regulatory network clarifies mechanisms of chronic inflammation and cancer evolution and offers novel therapeutic entry points for disorders ranging from asthma to pancreatic neuroendocrine carcinomas.