近日，英国剑桥大学教授Rahul Roychoudhuri及其课题组开发出阿司匹林通过限制血小板TXA2抑制T细胞免疫来防止转移。该项研究成果发表在2025年3月5日出版的《自然》上。

本研究表明，环氧化酶1（COX-1）抑制剂，包括阿司匹林，通过释放T细胞免受血小板源性血栓素A₂（TXA₂）的抑制，增强对癌症转移的免疫力。TXA₂作用于T细胞，触发依赖于鸟嘌呤交换因子ARHGEF1的免疫抑制途径，抑制T细胞受体驱动的激酶信号传导、增殖和效应功能。在小鼠中，T细胞特异性条件缺失Arhgef1会增加转移部位的T细胞活化，引发肺和肝转移的免疫介导排斥反应。因此，限制TXA₂主题阿司匹林、选择性COX-1抑制剂或血小板特异性COX-1缺失的可用性，以依赖于体内T细胞内在ARHGEF1表达和TXA₂信号传导的方式降低转移率。这些发现揭示了一种新的免疫抑制途径，限制了T细胞对癌症转移的免疫，为阿司匹林的抗转移活性提供了机制见解，并为更有效的抗转移免疫疗法铺平了道路。

据悉，转移是指癌细胞从原发肿瘤向远处器官的转移，是全球90%癌症死亡的主要原因。转移的癌细胞特别容易受到免疫攻击，因为它们最初被剥夺了在已建立的肿瘤中发现的免疫抑制微环境。有兴趣在治疗上利用这种免疫脆弱性，以防止复发的早期癌症患者的转移风险。

附：英文原文

Title: Aspirin prevents metastasis by limiting platelet TXA₂ suppression of T cell immunity

Author: Yang, Jie, Yamashita-Kanemaru, Yumi, Morris, Benjamin I., Contursi, Annalisa, Trajkovski, Daniel, Xu, Jingru, Patrascan, Ilinca, Benson, Jayme, Evans, Alexander C., Conti, Alberto G., Al-Deka, Aws, Dahmani, Layla, Avdic-Belltheus, Adnan, Zhang, Baojie, Okkenhaug, Hanneke, Whiteside, Sarah K., Imianowski, Charlotte J., Wesolowski, Alexander J., Webb, Louise V., Puccio, Simone, Tacconelli, Stefania, Bruno, Annalisa, Di Berardino, Sara, De Michele, Alessandra, Welch, Heidi C. E., Yu, I-Shing, Lin, Shu-Wha, Mitra, Suman, Lugli, Enrico, van der Weyden, Louise, Okkenhaug, Klaus, Saeb-Parsy, Kourosh, Patrignani, Paola, Adams, David J., Roychoudhuri, Rahul

Issue&Volume: 2025-03-05

Abstract: Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally1,2. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours3. There is interest in therapeutically exploiting this immune vulnerability to prevent recurrence in patients with early cancer at risk of metastasis. Here we show that inhibitors of cyclooxygenase 1 (COX-1), including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A₂ (TXA₂). TXA2 acts on T cells to trigger an immunosuppressive pathway that is dependent on the guanine exchange factor ARHGEF1, suppressing T cell receptor-driven kinase signalling, proliferation and effector functions. T cell-specific conditional deletion of Arhgef1 in mice increases T cell activation at the metastatic site, provoking immune-mediated rejection of lung and liver metastases. Consequently, restricting the availability of TXA₂ using aspirin, selective COX-1 inhibitors or platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner that is dependent on T cell-intrinsic expression of ARHGEF1 and signalling by TXA₂ in vivo. These findings reveal a novel immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.

DOI: 10.1038/s41586-025-08626-7

Source: https://www.nature.com/articles/s41586-025-08626-7