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Serotonin transporter SERT: a novel immune checkpoint for CD8+ T cell antitumor therapy

Qing Xiao1, Xinchun Zhang2, Xiaolong Liang3

  • 1Department of Hematology-Oncology, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China.

Journal for Immunotherapy of Cancer
|February 24, 2026
PubMed

Insights

Selective serotonin reuptake inhibitors (SSRIs) enhance T cell antitumor immunity by targeting the serotonin transporter (SERT). These antidepressants show promise in cancer immunotherapy, particularly with anti-PD-1 therapy.

Area of Science:

  • Immunology
  • Pharmacology
  • Oncology

Background:

  • The serotonin transporter (SERT) plays a role in regulating serotonin levels.
  • Intratumoral serotonin (5-HT) can suppress CD8+ T cell responses.
  • Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants.

Purpose of the Study:

  • To investigate the role of SERT in T cell-mediated antitumor immunity.
  • To evaluate the efficacy of SSRIs as cancer immunotherapy agents.
  • To explore the synergistic effects of SSRIs with anti-PD-1 therapy.

Main Methods:

  • Studies in mouse models and human xenografts.
  • Assessment of CD8+ T cell responses.
  • Evaluation of tumor growth inhibition.
  • Analysis of synergy with anti-PD-1 therapy.

Main Results:

  • SERT was found to suppress CD8+ T cell antitumor responses by depleting intratumoral 5-HT.
  • SSRIs significantly inhibited tumor growth and enhanced T cell-mediated antitumor immunity.
  • SSRIs demonstrated remarkable synergy with anti-PD-1 therapy.

Conclusions:

  • Intratumoral 5-HT signaling is crucial for antitumor immunity.
  • SERT acts as an immune checkpoint.
  • SSRIs are promising candidates for cancer immunotherapy, especially in combination with anti-PD-1 inhibitors.
Keywords:
Immune Checkpoint InhibitorImmunotherapyT cell

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