Uncovering Aspirin’s Mechanism to Reduce Cancer Metastasis in Mice

Uncovering Aspirin’s Mechanism to Reduce Cancer Metastasis in Mice

Posted on March 07, 2025 By News Team

An international research team headed by scientists at the University of Cambridge has uncovered a mechanism that may underpin how aspirin could reduce the metastasis of some cancers by preventing an immunosuppressive pathway that limits T-cell immunity. Reporting in Nature on their studies, including tests in mouse models of cancer, the researchers suggest that discovering the mechanism will support ongoing clinical trials, and could lead to the targeted use of aspirin to prevent the spread of susceptible types of cancer, and to the development of more effective immunotherapies to prevent cancer metastasis.

Research lead Rahul Roychoudhuri, PhD, at the University of Cambridge, said, “Most immunotherapies are developed to treat patients with established metastatic cancer, but when cancer first spreads there’s a unique therapeutic window of opportunity when cancer cells are particularly vulnerable to immune attack. We hope that therapies that target this window of vulnerability will have tremendous scope in preventing recurrence in patients with early cancer at risk of recurrence.”

The researchers described their work in a paper titled, “Aspirin prevents metastasis by limiting platelet TXA2 suppression of T cell immunity,” in which they say that their 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.”

Metastasis is the spread of cancer cells from primary tumors to distant organs and is the cause of 90% of cancer deaths globally,” the authors wrote. Roychoudhuri further noted, “Despite advances in cancer treatment, many patients with early-stage cancers receive treatments, such as surgical removal of the tumor, which have the potential to be curative, but later relapse due to the eventual growth of micrometastases—cancer cells that have seeded other parts of the body but remain in a latent state.”

Studies of people with cancer have previously observed that those taking daily low-dose aspirin have a reduction in the spread of some cancers, such as breast, bowel, and prostate cancers, and this has led to ongoing clinical trials. “Meta-analyses of large randomized controlled trials have shown that daily aspirin treatment is associated with reduction in metastasis at multiple sites in individuals with cancer,” the investigators wrote. However, until now it wasn’t known exactly how aspirin could prevent metastases.
In their newly reported study, the University of Cambridge-led team acknowledged that the discovery of how aspirin reduces cancer metastasis was serendipitous. The researchers were investigating the process of metastasis, and wanted to better understand how the immune system responds to metastasis, because when individual cancer cells break away from their originating tumor and spread to another part of the body, they are particularly vulnerable to immune attack. The immune system can recognize and kill these lone cancer cells more effectively than cancer cells within larger originating tumors, which have often developed an environment that suppresses the immune system. “Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumors,” they noted.
The researchers previously screened 810 genes in mice and found 15 that had an effect on cancer metastasis. In particular, they found that mice lacking a gene that produces a protein called ARHGEF1 had fewer metastases of various primary cancers to the lungs and liver.
The researchers determined that ARHGEF1 suppresses T cells that can recognize and kill metastatic cancer cells. The collective results of their experiments, they reported, “… show that ARHGEF1 functions intrinsically in T cells to limit effector functions and anti-metastatic immunity in vivo.”
To develop treatments that may take advantage of this discovery, the investigators needed to find a way for drugs to target it. “We sought to define upstream receptors and ligands that drive the immunosuppressive function of ARHGEF1 in T cells so as to reveal extracellular components of the pathway that might be amenable to therapeutic targeting,” they wrote.
The scientists traced signals in the cell to determine that ARHGEF1 is switched on when T cells are exposed to a clotting factor called thromboxane A2 (TXA2). This was an unexpected revelation for the scientists because TXA2 is already well-known and linked to how aspirin works. The findings, they commented “… suggest that ARHGEF1 has a critical role in transducing TXA2 signaling in T cells, limiting T cell activation and proliferation in response to T cell receptor (TCR) signaling.”
TXA2 is produced by platelets in the circulation that help blood to clot, preventing wounds from bleeding, but occasionally causing heart attacks and strokes. Aspirin reduces the production of TXA2, leading to the anti-clotting effects, which underlies its ability to prevent heart attacks and strokes. “The biosynthesis of TXA2 is blocked by inhibitors of COX enzymes, including aspirin,” the team explained. “Our observation that TXA2 limits T cell activation in an ARHGEF1-dependent manner in vitro led us to hypothesize that aspirin exerts an anti-metastatic effect by releasing T cells from TXA2-driven suppression mediated by ARHGEF1 in vivo.”
Their studies did then find that aspirin prevents cancers from spreading by decreasing TXA2 and releasing T cells from suppression. They used a mouse model of melanoma to show that in animals given aspirin, the frequency of metastases was reduced compared to control mice, and this was dependent on releasing T cells from suppression by TXA2.

 

Co-author Jie Yang, PhD, at the University of Cambridge, said: “It was a Eureka moment when we found TXA2 was the molecular signal that activates this suppressive effect on T cells. Before this, we had not been aware of the implication of our findings in understanding the anti-metastatic activity of aspirin. It was an entirely unexpected finding which sent us down quite a different path of inquiry than we had anticipated … Aspirin, or other drugs that could target this pathway, have the potential to be less expensive than antibody-based therapies, and therefore more accessible globally.”

In their paper, the team concluded: “This work establishes TXA2 as a regulator of T-cell immunity, with implications for cancer prevention and therapy. The identification of this pathway provides mechanistic insights into the anti-metastatic effects of aspirin, a potential basis for its more targeted use, and targets for development of new therapeutic strategies for preventing metastatic disease.”

In the future, the researchers plan to help the translation of their work into potential clinical practice by collaborating with Ruth Langley, MD, professor of oncology & clinical trials at the MRC Clinical Trials Unit at University College London, and who is leading the Add-Aspirin clinical trial, to find out if aspirin can stop or delay early stage cancers from coming back. Langley, who was not involved in the newly reported study, commented, “This is an important discovery. It will enable us to interpret the results of ongoing clinical trials and work out who is most likely to benefit from aspirin after a cancer diagnosis.”

The scientists caution that, in some people, aspirin can have serious side effects and clinical trials are underway to determine how to use it safely and effectively to prevent cancer spread, so people should consult their doctor before starting to take it. “In a small proportion of people, aspirin can cause serious side effects, including bleeding or stomach ulcers,” Langley said. “Therefore, it is important to understand which people with cancer are likely to benefit and always talk to your doctor before starting aspirin.”

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