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 |
| Topics | Serotonin |
| 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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cites 7
- LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: A qualitative study of acute and sustained subjective effects Journal of Psychopharmacology November 11, 2014
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- Modern Clinical Research on LSD Neuropsychopharmacology April 27, 2017
- Therapeutic use of classic psychedelics to treat cancer-related psychiatric distress International Review of Psychiatry July 4, 2018
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews November 30, 2023
and 2 more in the library