Blocking serotonin transporters with antidepressants boosted CD8 T cell function and enhanced immunotherapy response in mouse and human tumor models.
Serotonin transporter (SERT) acted as an immune checkpoint in tumors, according to study findings published in Cell, and inhibiting SERT with selective serotonin reuptake inhibitors — a class of antidepressants — boosted CD8 T cell antitumor activity in not just mouse, but also human tumor models.
“It turns out selective serotonin reuptake inhibitors don’t just make our brains happier; they also make our T cells happier — even while they’re fighting tumors,” Dr. Lili Yang, senior author of the study, said in a news release from UCLA. “These drugs have been widely and safely used to treat depression for decades, so repurposing them for cancer would be a lot easier than developing an entirely new therapy.”
Yang serves as a professor of Microbiology, Immunology and Molecular Genetics, and is a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, UCLA Health.
It turns out selective serotonin reuptake inhibitors don’t just make our brains happier; they also make our T cells happier — even while they’re fighting tumors.
In addition, treatment with selective serotonin reuptake inhibitors enhanced the effect of treatment with anti-PD-1 therapy, and high levels of SERT — an intratumoral serotonin transporter — within tumors were linked with worse survival. This connection was seen in various solid tumor models including melanoma, breast cancer, lung cancer, kidney cancer and sarcoma.
These results suggest the serotonin pathway plays a key role in immune regulation and support further exploration of selective serotonin reuptake inhibitors as potential tools in cancer immunotherapy, according to study authors.
SERT is a key part of the serotonin axis that regulates serotonin concentrations by transporting serotonin from the extracellular to the intracellular environment. Although SERT is widely studied in the brain for its role in mood and behavior, it also plays an important role in immune cells and peripheral tissues, where it helps control serotonin’s effects on inflammation, metabolism and tissue repair. Because SERT controls how much serotonin is available outside the cell, it is a primary drug target for medications that aim to adjust serotonin signaling.
CD8 T cells: immune cells that kill cancer cells.
Immune checkpoint: molecule that can slow down immune responses; SERT acts as one in tumors.
PD-1 blockade: type of immunotherapy that removes brakes on immune cells, helping them attack cancer.
Serotonin axis: system that controls how serotonin functions in the body, including in the immune system.
Selective serotonin reuptake inhibitors, also known as SSRIs, are the most commonly prescribed class of antidepressants, designed to increase serotonin levels outside cells by blocking SERT, the protein that transports serotonin back inside. By doing this, selective serotonin reuptake inhibitors boost serotonin’s ability to activate its receptors, which can improve mood and emotional well-being. Medications like Prozac (fluoxetine), Celexa (citalopram) and Zoloft (sertraline) fall into this category.
Beyond their use in treating depression, selective serotonin reuptake inhibitors are being studied for their potential to affect the immune system and possibly support cancer immunotherapy by influencing how serotonin behaves in the tumor environment.
Researchers previously identified MAO-A, an enzyme that breaks down serotonin, as a player in shaping immune responses to cancer. In this study, they reveal that the serotonin axis within tumors plays a key role in how CD8 T cells fight cancer. The team found that SERT acts as a powerful brake on this immune activity, making it a beneficial new immune checkpoint target. In contrast to its role in the nervous system, SERT functions differently in tumor-infiltrating T cells due to dynamic expression patterns, local serotonin signaling and distinct receptor pathways.
Building on earlier findings that these antidepressants can boost antitumor immunity by blocking monoamine breakdown, the study now shows that selective serotonin reuptake inhibitors — which selectively inhibit SERT — achieve similar or better immune effects with fewer risks. Unlike MAOIs, which can cause serious side effects, selective serotonin reuptake inhibitors avoided toxic immune reactions and behavioral issues in mice.
These results position selective serotonin reuptake inhibitors as safer and more effective tools for harnessing the serotonin pathway in future cancer immunotherapy strategies.
"Together, the human T cell and clinical correlation data support our model of SERT-mediated negative regulation of human antitumor CD8 T cell immunity and position SSRI antidepressants as promising candidates for next-generation cancer immunotherapy," Yang and colleagues concluded in the journal.
“Serotonin transporter inhibits antitumor immunity through regulating the intratumoral serotonin axis” by Dr. Bo Li, et al., Cell.
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