2025/03/05 by Jie Yang, Yumi Yamashita-Kanemaru, Benjamin I. Morris +32 · 1 voice · 5 citations
Medicine · Immunology and Microbiology · #Inflammatory mediators and NSAID effects #Chemokine receptors and signaling #Mast cells and histamine
paper · pdf · 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 1,2 . Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours 3 . 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 2 (TXA 2 ). TXA 2 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 2 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 2 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.