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

Jie Yang (), Yumi Yamashita-Kanemaru, Benjamin I. Morris, Annalisa Contursi, Daniel Trajkovski, Jingru Xu, Ilinca Patrascan, Jayme Benson, Alexander C. Evans, Alberto G. Conti, Aws Al-Deka, Layla Dahmani, Adnan Avdic-Belltheus, Baojie Zhang, Hanneke Okkenhaug, Sarah K. Whiteside, Charlotte J. Imianowski, Alexander J. Wesolowski, Louise V. Webb, Simone Puccio, Stefania Tacconelli, Annalisa Bruno, Sara Berardino, Alessandra Michele, Heidi C. E. Welch, I-Shing Yu, Shu-Wha Lin, Suman Mitra, Enrico Lugli, Louise Weyden, Klaus Okkenhaug, Kourosh Saeb-Parsy, Paola Patrignani, David J. Adams and Rahul Roychoudhuri ()
Additional contact information
Jie Yang: University of Cambridge
Yumi Yamashita-Kanemaru: University of Cambridge
Benjamin I. Morris: University of Cambridge
Annalisa Contursi: “G. d’Annunzio” University of Chieti-Pescara
Daniel Trajkovski: University of Cambridge and NIHR Cambridge Biomedical Research Centre
Jingru Xu: University of Cambridge
Ilinca Patrascan: University of Cambridge
Jayme Benson: University of Cambridge
Alexander C. Evans: University of Cambridge
Alberto G. Conti: University of Cambridge
Aws Al-Deka: University of Cambridge
Layla Dahmani: University of Cambridge
Adnan Avdic-Belltheus: University of Cambridge
Baojie Zhang: University of Cambridge
Hanneke Okkenhaug: Babraham Institute
Sarah K. Whiteside: University of Cambridge
Charlotte J. Imianowski: University of Cambridge
Alexander J. Wesolowski: University of Cambridge
Louise V. Webb: Francis Crick Institute
Simone Puccio: IRCCS Humanitas Research Hospital
Stefania Tacconelli: “G. d’Annunzio” University of Chieti-Pescara
Annalisa Bruno: “G. d’Annunzio” University of Chieti-Pescara
Sara Berardino: “G. d’Annunzio” University of Chieti-Pescara
Alessandra Michele: “G. d’Annunzio” University of Chieti-Pescara
Heidi C. E. Welch: Babraham Institute
I-Shing Yu: National Taiwan University
Shu-Wha Lin: National Taiwan University
Suman Mitra: Lille University Hospital
Enrico Lugli: IRCCS Humanitas Research Hospital
Louise Weyden: Wellcome Genome Campus
Klaus Okkenhaug: University of Cambridge
Kourosh Saeb-Parsy: University of Cambridge and NIHR Cambridge Biomedical Research Centre
Paola Patrignani: “G. d’Annunzio” University of Chieti-Pescara
David J. Adams: Wellcome Genome Campus
Rahul Roychoudhuri: University of Cambridge

Nature, 2025, vol. 640, issue 8060, 1052-1061

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-08626-7

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