Targeting peripheral 5-HT(2A)R enhances antitumor immunity in colorectal cancer.
Cancer remains a leading cause of morbidity and mortality worldwide. While classical psychedelics have been used clinically to treat cancer-associated psychiatric disorders, their impact on tumor progression is unclear. Here, we show that by targeting the serotonin receptor 5-HT2
- Authors
- Wen Y, Tang L, Duan W, Ren Q, Ni Y, Chen S, Chen J, Yang L, Wang H, Chen Y, Zheng Y, Pan X, Du H, Huang M, Zeng A, Zhou Z, Zhang Z, Ji H, Ge G, Zeng YA, Zhang W, Wang S, Cheng J, Wang S, Chen J
- Journal
- Cell
- Published
- 2026-08-04
- DOI
- 10.1016/j.cell.2026.07.028
- PMID
- 42551424
- Content type
- Paper
- Authority
- Academic
Abstract
Cancer remains a leading cause of morbidity and mortality worldwide. While classical psychedelics have been used clinically to treat cancer-associated psychiatric disorders, their impact on tumor progression is unclear. Here, we show that by targeting the serotonin receptor 5-HT2AR, lysergic acid diethylamide (LSD) enhances CD8+ T cell-mediated antitumor immunity and suppresses colorectal cancer (CRC) growth. To harness this activity while avoiding psychedelic effects, we developed IHCH-8110, a non-brain-penetrant 5-HT2AR agonist that selectively targets peripheral 5-HT2AR. We show that IHCH-8110 inhibits CRC progression by activating 5-HT2AR on enteric glial cells, thereby inducing CXCL10 and interleukin (IL)-18 expression to promote CD8+ T cell recruitment and effector polarization within the tumor microenvironment. By converting immune-cold CRC into a more immunologically responsive state, IHCH-8110 enhances the efficacy of PD-1 blockade. Together, our findings identify enteric 5-HT2AR signaling as a regulator of antitumor immunity and support peripheral 5-HT2AR agonists as a therapeutic strategy for CRC immunotherapy.
Citation
Wen Y, Tang L, Duan W, Ren Q, Ni Y, Chen S, Chen J, Yang L, Wang H, Chen Y, Zheng Y, Pan X, Du H, Huang M, Zeng A, Zhou Z, Zhang Z, Ji H, Ge G, Zeng YA, Zhang W, Wang S, Cheng J, Wang S, Chen J (2026) Targeting peripheral 5-HT(2A)R enhances antitumor immunity in colorectal cancer.. Cell. doi:10.1016/j.cell.2026.07.028
DOI: 10.1016/j.cell.2026.07.028
Indexed by the DMT Code Research Bibliography, an open, stance scored library (CC-BY-4.0).