The neurotransmitter 5-hydroxytryptamine (5-HT) promotes gastrointestinal inflammation, a process that can facilitate development of colitis-associated cancer. Li and Fu et al. find that the rate-limiting enzyme in 5-HT synthesis is upregulated in tumor tissues of mouse models, as well as patients with colorectal cancer. Tumor cell–derived 5-HT leads to inflammasome activation in macrophages via HTR3A (5-hydroxytryptamine receptor 3A), an ion channel receptor, and the resulting calcium influx. Interestingly, inflammasome-mediated IL1β release from macrophages then further promotes tumor cell 5-HT production, demonstrating a positive feedback loop that has potential to be therapeutically targeted. Read more in this issue on page 1008. Original image from Fig. 7I. Artwork by Lewis Long.