Role of serotonin receptor signaling in cancer cells and anti-tumor immunity

Abstract

Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter known to affect emotion, behavior, and cognition, and its effects are mostly studied in neurological diseases. The crosstalk between the immune cells and the nervous system through serotonin and its receptors (5-HTRs) in the tumor microenvironment and the secondary lymphoid organs are known to affect cancer pathogenesis. However, the molecular mechanism of - alteration in the phenotype and function of - innate and adaptive immune cells by serotonin is not well explored. In this review, we discuss how serotonin and serotonin receptors modulate the phenotype and function of various immune cells, and how the 5-HT-5-HTR axis modulates antitumor immunity. Understanding how 5-HT and immune signaling are involved in tumor immunity could help improve therapeutic strategies to control cancer progression and metastasis.

Keywords: 5-hydroxytryptamine; neuroimmune communication; neurotransmitter; serotonergic system; serotonin receptor.

Figure 1

Synthesis of peripheral serotonin. Serotonin is synthesized from L-tryptophan by the TPH1 enzyme in the enterochromaffin cells of the intestinal epithelium, which is taken up by platelets and mast cells present in the local circulation. They release the serotonin elsewhere in the body either upon stimulation or due to their rupture.

Figure 2

Signaling pathways of the serotonin receptor (5-HTR) subtypes. Serotonin signals through 15 receptor subtypes. Most of the receptors belong to GPCRs except the 5-HTR3 subfamily. These receptors activate four major interconnected signaling networks: PI3K/Akt, PKC/Ca²⁺, MAPK, and PKA-cAMP axis. Here, solid black arrows indicate stimulation of a pathway and black dashed arrows indicate inhibition of a pathway.

Figure 3

Effects of serotonin signaling on different components of the immune system. Serotonin signaling stimulates activation and proliferation of T cells, promotes maturation of DCs, supports B cell development, enhances cytotoxicity of NK cells, and stimulates polarization of macrophages toward the M2 phenotype. On the other hand, serotonin signaling inhibits M1 macrophage polarization. Here, solid black arrows indicate stimulation and black dashed arrows indicate inhibition, and green upward arrows indicate an increase in cytokine secretion, and red downward arrows indicate a decrease in cytokine secretion.

Figure 4

Effects of serotonin signaling on cancer. Serotonin signaling promotes tumor progression by stimulating proliferation and inhibiting apoptosis of cancer cells via MAPK and PI3K/Akt signaling axis. Here, solid black arrows indicate stimulation and dashed black arrows indicate inhibition. Abbreviations: BC, Breast cancer; CC, Colon cancer; HCC, Hepatocellular carcinoma; PC, Prostate cancer.