Targeting peripheral 5-HT2AR enhances antitumor immunity in colorectal cancer.
Yating Wen, Lingjie Tang, Wenwen Duan, Qingfei Ren, Yangyue Ni, Shi-Yang Chen, Jun Chen, Lei Yang, Huan Wang, Yuan Chen, Yun-zhe Zheng, Xingchao Pan, Hui Du, Meng-wen Huang, An Zeng, Zhaocai Zhou, Zhigang Zhang, Hongbin Ji, Gaoxiang Ge, Y. A. Zeng, Wei Zhang, Shihui Wang, Jianjun Cheng, Sheng Wang, Jianfeng Chen
Cell August 1, 2026 DOI: 10.1016/j.cell.2026.07.028 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Colorectal cancer models |
| Interventions | LSD IHCH-8110 |
| Key points | LSD and the non-brain-penetrant 5-HT2AR agonist IHCH-8110 suppress colorectal cancer growth by activating 5-HT2AR on enteric glial cells, inducing CXCL10 and IL-18 to promote CD8+ T cell recruitment and effector polarization, thereby enhancing PD-1 blockade efficacy. |
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.