Targeting peripheral 5-HT2AR enhances antitumor immunity in colorectal cancer.

Cancer research · Colorectal cancer

Targeting peripheral 5-HT2AR enhances antitumor immunity in colorectal cancer.

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. IHCH‑8110 inhibits CRC progression by activating 5-HT2AR on enteric glial cells, thereby inducing CXCL10 and interleukin‑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.

This study demonstrates that selective peripheral activation of the serotonin receptor 5‑HT2AR can boost anti‑tumor immune responses and improve the effectiveness of checkpoint blockade in colorectal cancer.

Evidence level: Állatkísérletes. Állatmodellben vizsgálták.

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