Serotonin transporter inhibits antitumor immunity through regulating the intratumoral serotonin axis

Affiliations

• 1. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: bo.li@ucla.edu.
• 2. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
• 3. Department of Materials Science and Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.
• 4. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
• 5. Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.
• 6. Department of Urology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
• 7. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute for Quantitative and Computational Biosciences-The Collaboratory, University of California, Los Angeles, Los Angeles, CA 90095, USA.
• 8. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Goodman-Luskin Microbiome Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: liliyang@ucla.edu.

PMID: 40403728  PMCID: PMC12255530  DOI: 10.1016/j.cell.2025.04.032

Abstract

Identifying additional immune checkpoints hindering antitumor T cell responses is key to the development of next-generation cancer immunotherapies. Here, we report the induction of serotonin transporter (SERT), a regulator of serotonin levels and physiological functions in the brain and peripheral tissues, in tumor-infiltrating CD8 T cells. Inhibition of SERT using selective serotonin reuptake inhibitors (SSRIs), the most widely prescribed antidepressants, significantly suppressed tumor growth and enhanced T cell antitumor immunity in various mouse syngeneic and human xenograft tumor models. Importantly, SSRI treatment exhibited significant therapeutic synergy with programmed cell death protein 1 (PD-1) blockade, and clinical data correlation studies negatively associated intratumoral SERT expression with patient survival in a range of cancers. Mechanistically, SERT functions as a negative-feedback regulator inhibiting CD8 T cell reactivities by depleting intratumoral T cell-autocrine serotonin. These findings highlight the significance of the intratumoral serotonin axis and identify SERT as an immune checkpoint, positioning SSRIs as promising candidates for cancer immunotherapy.

摘要

识别阻碍抗肿瘤T细胞反应的额外免疫检查点是开发下一代癌症免疫疗法的关键。本研究报道，在肿瘤浸润的CD8+ T细胞中诱导表达了血清素转运体（Sertotonin Transporter, SERT），SERT是大脑和外周组织中调节血清素水平和生理功能的关键分子。使用选择性血清素再摄取抑制剂（Selective Serotonin Reuptake Inhibitors, SSRIs）（目前最常用的抗抑郁药物）抑制SERT，在多种小鼠同系肿瘤模型和人源肿瘤异种移植模型中，均能显著抑制肿瘤生长并增强T细胞的抗肿瘤免疫力。重要的是，SSRI治疗与程序性细胞死亡蛋白1（Programmed Cell Death Protein 1, PD-1）阻断疗法表现出显著的协同治疗效果；临床数据相关性分析显示，在多种癌症中，瘤内SERT表达水平与患者生存率呈负相关。从机制上讲，SERT通过耗竭肿瘤内T细胞自分泌的血清素，发挥抑制CD8+ T细胞反应性的负反馈调节因子作用。这些发现揭示了瘤内血清素信号轴在抗肿瘤免疫中的重要意义，并将SERT确立为一个新型免疫检查点，从而将SSRIs定位为癌症免疫治疗领域极具前景的候选药物。

Keywords: PD-1 blockade; SSRIs; T cell antitumor immunity; antidepressants; cancer immunotherapy; immune checkpoint; intratumoral serotonin axis; serotonin; serotonin transporter; tumor microenvironment.

关键词：PD-1阻断、血清素再摄取抑制剂、T细胞抗肿瘤免疫、抗抑郁药、癌症免疫疗法、免疫检查点、瘤内血清素轴、血清素、血清素转运体、肿瘤微环境、鼠抗、兔单抗、流式抗体、佰乐博、佰乐博生物