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From the Journals

Early Research Finds Aspirin May Block Cancer Spread by Boosting Immune Response

Preclinical study demonstrates that aspirin may prevent cancer metastasis by inhibiting platelet-produced TXA2, which normally suppresses T-cell immunity against spreading cancer cells.

Conexiant

A new study revealed potential insights into the molecular mechanism behind aspirin’s anti-neoplastic effects. Researchers from the University of Cambridge and international collaborators have provided mechanistic evidence that aspirin may prevent cancer metastasis by inhibiting platelet-derived thromboxane A2 production, thereby preventing the suppression of T cell–mediated immune responses against metastasizing cancer cells.

The study's investigators identified a previously unknown immunosuppressive pathway in which platelet-derived thromboxane A2 (TXA2) activates the TP receptor on T cells, leading to ARHGEF1-dependent suppression of immune surveillance against cancer metastasis. These findings provide mechanistic insights into previously observed epidemiological data that showed reduced metastatic recurrence in patients with cancer taking daily aspirin. Results were published in Nature.

“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,” wrote lead authors Jie Yang, PhD, and Rahul Roychoudhuri, PhD, both of the University of Cambridge, and their colleagues.

Molecular Mechanism

Metastasis is responsible for approximately 90% of cancer-related deaths worldwide. Metastasizing cancer cells are particularly susceptible to immune attack when they first disseminate, as they lack the immunosuppressive microenvironment found in established tumors.

Previous meta-analyses of large randomized controlled trials have reported that daily aspirin treatment is associated with reduced metastasis to multiple sites in patients with cancer (hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.48–0.84). Additionally, low-dose aspirin treatment (75–300 mg) has been associated with reduced cancer-specific mortality in individuals without metastasis at diagnosis (HR = 0.49, 95% CI = 0.30–0.79).

In the current study, researchers discovered that TXA2 signaling suppresses T cell receptor–driven kinase activation, proliferation, and effector functions via an ARHGEF1-dependent pathway. When mice with T cell–specific deletion of ARHGEF1 were studied, they exhibited increased T cell activation at metastatic sites and enhanced rejection of lung and liver metastases.

Additional Research

The researchers conducted multiple experiments demonstrating that aspirin and selective COX-1 inhibitors reduced metastasis in a manner dependent on T cell–intrinsic ARHGEF1 expression and TXA2 signaling:

  • Mice with T cell–specific deletion of ARHGEF1 exhibited reduced metastatic burden in both lung and liver metastasis models.

  • Treatment with aspirin or selective COX-1 inhibitors significantly decreased metastasis frequency in control mice but not in mice with T cell–specific ARHGEF1 deletion.

  • Platelet-specific deletion of COX-1 (the enzyme required for TXA2 production) resulted in markedly reduced metastasis and decreased urinary abundance of TXA2 metabolites.

  • Supplementation of aspirin-treated mice with a TXA2 analog reversed aspirin’s anti-metastatic effects, confirming TXA2’s critical role in metastasis suppression.

At the molecular level, the researchers found that TXA2 activates ARHGEF1, which then stimulates RHOA signaling in T cells, suppressing T cell receptor–driven PI3K and MAPK pathways and limiting T cell activation against metastasizing cancer cells.

Clinical Implications

The study suggests that aspirin’s anti-metastatic effects are primarily mediated through inhibition of platelet COX-1 rather than COX-2. This distinction supports the development of more selective approaches targeting this pathway to prevent metastatic recurrence, while potentially reducing aspirin-associated risks such as bleeding and gastric toxicity.

“Although aspirin provides a potentially attractive opportunity for anti-metastatic therapy given its low cost, more selective targeting of the TXA2–ARHGEF1 pathway could enable enhanced anti-metastatic activity and/or reduced bleeding risk and gastric toxicity,” the authors noted.

Furthermore, these findings suggest that aspirin might synergize with other adjuvant immunotherapies and that biomarkers related to this pathway could help identify patients most likely to benefit from aspirin’s anti-metastatic effects.

Dr. Roychoudhuri serves as a scientific advisor for Enhanc3D Genomics and OligoTune Ltd and collaborates on industry-funded projects with AstraZeneca PLC and F-Star Therapeutics, all on topics unrelated to this study. Dr. Lugli has received research grants from Bristol Myers Squibb for work unrelated to this study and has acted as a consultant for BD Biosciences. The remaining authors declared no competing interests.