ArticleProceedings of the National Academy of Sciences of the United States of America2013
Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 200 papers.
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200 citing papers in PubMed, 337 citations in OpenAlex.
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- Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.bioRxiv : the preprint server for biology · 2026Article
- The CD73-adenosine axis in melanoma: from multidimensional regulation to precision immunotherapy.Frontiers in immunology · 2026Review
- CD73 expression as a resistance mechanism in advancedFrontiers in oncology · 2026Article
- Expression and prognostic importance of lymphocyte activation gene 3 and CD73 in advanced or metastatic hepatocellular carcinoma.The Journal of international medical research · 2026Article
- Harnessing the Power of CAR-NK Cells for Solid Tumors: Challenges, Innovations, and Future Frontiers in Immunotherapy.Cancer communications (London, England) · 2026Review
- CD39 and CD73: biological functions, diseases and therapy.Molecular biomedicine · 2025Review
- Anticancer Activity of Triterpene Glycosides Cucumarioside AInternational journal of molecular sciences · 2025Article
- Natural Killer Cell-Mediated Antitumor Immunity: Molecular Mechanisms and Clinical Applications.MedComm · 2025Review
- Tumor site-directed A1R expression enhances CAR T cell function and improves efficacy against solid tumors.Nature communications · 2025Article
- Deciphering adenosine signaling in hepatocellular carcinoma: Pathways, prognostic models, and therapeutic implications.Clinical and molecular hepatology · 2025Review
- Therapeutic potential of adenosine receptor modulators in cancer treatment.RSC advances · 2025Review
- Insights from Clinical Trials on AACS pharmacology & translational science · 2025Review
- Bioactive polydopamine nanomedicines-assisted cancer immunotherapy.Materials today. Bio · 2025Review
- Oxygen-carrying nanoemulsions and respiratory hyperoxia eliminate tumor hypoxia-induced immunosuppression.JCI insight · 2025Article
- Predicting recurrence in adult granulosa cell tumors: the role of Ki67, p53, and TERT mutations.Archives of gynecology and obstetrics · 2025Article
- Adenosine receptors on the immuno-oncology expressway: TIME, perspectives, and translation.Frontiers in immunology · 2025Review
140 more citing papers are in PubMed but not listed here.
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10 authors at 3 institutions in 2 countries.
Funding
Abstract
CD73 inhibits antitumor immunity through the activation of adenosine receptors expressed on multiple immune subsets. CD73 also enhances tumor metastasis, although the nature of the immune subsets and adenosine receptor subtypes involved in this process are largely unknown. In this study, we revealed that A2A/A2B receptor antagonists were effective in reducing the metastasis of tumors expressing CD73 endogenously (4T1.2 breast tumors) and when CD73 was ectopically expressed (B16F10 melanoma). A2A(-/-) mice were strongly protected against tumor metastasis, indicating that host A2A receptors enhanced tumor metastasis. A2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A2A blockade was due to enhanced NK cell function. Interestingly, A2B blockade had no effect on NK cell cytotoxicity, indicating that an NK cell-independent mechanism also contributed to the increased metastasis of CD73(+) tumors. Our results thus revealed that CD73 promotes tumor metastasis through multiple mechanisms, including suppression of NK cell function. Furthermore, our data strongly suggest that A2A or A2B antagonists may be useful for the treatment of metastatic disease. Overall, our study has potential therapeutic implications given that A2A/A2B receptor antagonists have already entered clinical trials in other therapeutic settings.
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