Peripheral serotonergic signaling has been implicated in diverse physiological processes, yet its role in coordinating glial-immune interactions remains poorly understood. In this issue of Cell, Wen and colleagues identify enteric glial cells as critical effectors of peripheral 5-HT2AR agonism, uncovering a serotonergic neuroimmune circuit that drives cytotoxic T cell-mediated immunity against colorectal cancer.