Aspirin prevents metastasis by limiting platelet TXA suppression of T cell immunity.
Journal
Nature
Journal Volume
640
Journal Issue
8060
Start Page
1052
End Page
1061
ISSN
1476-4687
Date Issued
2025-04
Author(s)
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
Mitra, Suman
Lugli, Enrico
van der Weyden, Louise
Okkenhaug, Klaus
Saeb-Parsy, Kourosh
Patrignani, Paola
Adams, David J
Roychoudhuri, Rahul
DOI
10.1038/s41586-025-08626-7
Abstract
Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours. 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 A (TXA). TXA 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 TXA 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 TXA 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.
SDGs
Publisher
Nature Research
Description
Article number 3
Type
journal article