How Does Aspirin Block Cancer Metastasis?

 Daily low-dose aspirin may prevent cancer metastasis by inhibiting platelet activation, thereby enhancing T cell-mediated immunity. This mechanism provides clinicians with a potential biomarker-guided approach to identify patients who are most likely to benefit while carefully balancing risks, such as bleeding.

Over the past 50 years, several studies have demonstrated that aspirin reduces cancer growth and dissemination, particularly in gastrointestinal cancers such as colorectal and gastric cancers. However, the underlying biological mechanisms have remained elusive.

A recent study by Jie Yang from the Department of Pathology at the University of Cambridge, Cambridge, England, and colleagues, published in Nature, elucidated that aspirin prevents metastasis by suppressing platelet-derived thromboxane A₂ (TXA₂).

Activated platelets release TXA₂, which signals the key effectors of T lymphocytes in tumour cell elimination to retract, thus facilitating metastatic progression. Central to this pro-metastatic pathway is the protein ARHGEF1, which is activated by TXA₂ in T cells.

Activated platelets release TXA₂, which signals T lymphocytes — key effectors in tumour cell elimination — to retract, thereby facilitating metastatic progression. Central to this pro-metastatic pathway is the protein ARHGEF1, which is activated by TXA₂ in T cells.

Aspirin irreversibly inhibits COX-1, blocking the synthesis of thromboxane A. In murine models, administration of the TXA₂ analogue U46619 increased metastasis, whereas low-dose aspirin administered in drinking water at human-equivalent doses significantly reduced metastasis.

This protective effect was not observed in mice with T-cell-specific deletion of ARHGEF1, confirming that the benefits of aspirin are mediated via T-lymphocyte ARHGEF1 signalling.

In a companion review in The New England Journal of Medicine, Ruth E. Langley, MB, BS, PhD, from the Medical Research Council Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London (UCL), London, and John Burn, MD, from the Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, England, described the work of the newly formed Suppressing Platelet Activation to Reduce Cancer (SPARC) collaboration. SPARC is an international multidisciplinary group led by UCL and funded by Cancer Research UK. The focus is on understanding how aspirin can be best used to prevent cancer. The group brings together experts in aspirin pharmacology, cutting-edge molecular genetics, and clinical researchers to focus on answering the question: “How does aspirin prevent cancer?”

The authors emphasised that aspirin is an inexpensive, generic drug amid rising global cancer incidence, especially in low- and middle-income countries. However, without pharmaceutical sponsorship for licence extension, off-label aspirin use for the primary or secondary prevention of metastasis remains constrained.

The TXA₂-T-cell axis suggests that the efficacy of aspirin is greatest in immunogenic tumours. Supporting evidence includes long-term trials showing that aspirin prevents mismatch repair-deficient cancers in Lynch syndrome (which is highly immunogenic).

The ALASCCA trial suggested that it is possible to identify patients most likely to benefit from aspirin after surgery based on the genetic characteristics of their cancer. In this trial, aspirin resulted in a significantly lower incidence of colorectal cancer recurrence than placebo in patients with phosphatidylinositol 3-kinase-mutated colorectal cancer.

Additionally, in a large cohort study evaluating aspirin use after colorectal cancer resection, the expression of class I human leucocyte antigen in the primary tumour was associated with improved overall survival in patients treated with aspirin.

Tracy Smith, Trustee of Lynch Syndrome UK, said, “For families living with hereditary cancer risk, this research offers real hope. Understanding how aspirin works to suppress platelet activation means that we are closer to knowing who can benefit the most and how to use it safely. Every step forward gives patients more confidence, more choices, and more time — and that is invaluable.”

However, further studies are required to fully understand the relationship between platelet activation and cancer prevention. Aspirin does increase the risk for bleeding, and individuals should not start taking regular aspirin without first discussing it with a healthcare professional.

https://www.medscape.com/viewarticle/how-does-aspirin-block-cancer-metastasis-2026a10002zb