Serotonin (5-HT): ancient signaling molecule reshaped by serotonylation in cancer

Serotonin (5-HT), a conserved monoamine derived from tryptophan metabolism, has emerged as a multifaceted regulator in cancer biology. Beyond receptor signaling, serotonylation allows transglutaminase 2 (TGM2) to covalently incorporate serotonin into target proteins, linking intracellular serotonin availability to regulation of tumor metabolism, chromatin state, and immune function. Despite recent progress, the determinants of substrate selection and the physiological scope of serotonylation remain incompletely defined. In this review, we integrate advances in serotonin metabolism and receptor signaling with emerging insights into serotonylation, emphasizing its roles in tumors and the tumor microenvironment, and outline priorities for future investigation.