Li Bo, Elsten-Brown James, Li Miao, Zhu Enbo, Li Zhe, Chen Yuning, Kang Elliot, Ma Feiyang, Chiang Jennifer, Li Yan-Ruide, Zhu Yichen, Huang Jie, Fung Audrey, Scarborough Quentin, Cadd Robin, Zhou Jin J, Chin Arnold I, Pellegrini Matteo, Yang Lili
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell. 2025 Jul 10;188(14):3823-3842.e21. doi: 10.1016/j.cell.2025.04.032. Epub 2025 May 21.
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.
识别阻碍抗肿瘤T细胞反应的其他免疫检查点是开发下一代癌症免疫疗法的关键。在此，我们报告了血清素转运体（SERT）在肿瘤浸润性CD8 T细胞中的诱导情况，SERT是大脑和外周组织中血清素水平及生理功能的调节因子。使用选择性5-羟色胺再摄取抑制剂（SSRI，最广泛使用的抗抑郁药）抑制SERT，在多种小鼠同基因和人异种移植肿瘤模型中显著抑制了肿瘤生长并增强了T细胞抗肿瘤免疫力。重要的是，SSRI治疗与程序性细胞死亡蛋白1（PD-1）阻断表现出显著的治疗协同作用，临床数据相关性研究表明肿瘤内SERT表达与多种癌症患者的生存率呈负相关。从机制上讲，SERT通过消耗肿瘤内T细胞自分泌的血清素，作为负反馈调节因子抑制CD8 T细胞反应性。这些发现突出了肿瘤内血清素轴的重要性，并将SERT识别为一个免疫检查点，将SSRI定位为癌症免疫疗法的有前景的候选药物。
