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Targeting peripheral 5-HT2AR enhances antitumor immunity in colorectal cancer

YaTing Wen1, LingJie Tang2, WenWen Duan3

  • 1Frontier Innovation Center, Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Systems Medicine for Cancer, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Fudan University, Shanghai 200032, China; Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.

Cell
|August 4, 2026
PubMed

Insights

Lysergic acid diethylamide (LSD) and a novel compound, IHCH-8110, enhance the immune system's ability to fight colorectal cancer (CRC). IHCH-8110 activates peripheral serotonin receptors to boost T cell responses against tumors.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Cancer is a major global health burden.
  • Classical psychedelics show potential in managing cancer-related psychological distress, but their direct effects on tumor growth are not well understood.
  • The serotonin receptor 5-HT2AR is implicated in various biological processes.

Purpose of the Study:

  • To investigate the impact of targeting the 5-HT2AR on colorectal cancer (CRC) progression and antitumor immunity.
  • To develop a peripherally acting 5-HT2AR agonist to harness therapeutic benefits while minimizing central nervous system effects.

Main Methods:

  • Administration of lysergic acid diethylamide (LSD) and a novel compound, IHCH-8110, in preclinical models.
  • Analysis of immune cell infiltration and activation within the tumor microenvironment.
  • Assessment of tumor growth and response to immunotherapy, including PD-1 blockade.

Main Results:

  • LSD and IHCH-8110 enhance CD8+ T cell-mediated antitumor immunity.
  • IHCH-8110 selectively activates peripheral 5-HT2AR on enteric glial cells, inducing CXCL10 and IL-18.
  • This leads to increased CD8+ T cell recruitment and effector function, converting immune-cold tumors into a more responsive state.
  • IHCH-8110 improves the efficacy of PD-1 blockade in CRC models.

Conclusions:

  • Peripheral 5-HT2AR signaling regulates antitumor immunity in colorectal cancer.
  • IHCH-8110, a non-brain-penetrant 5-HT2AR agonist, shows therapeutic potential for CRC immunotherapy.
  • Targeting enteric 5-HT2AR represents a promising strategy to enhance immune responses against colorectal cancer.
Keywords:
5-HT(2A)R agonistcolorectal cancercytotoxic CD8(+) T cellenteric glial cell

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