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Remley et al. Cancer Drug Resist 2023;6:748-67 Cancer
DOI: 10.20517/cdr.2023.63
Drug Resistance

Review Open Access

Unlocking antitumor immunity with adenosine

receptor blockers

2
1,3
Victoria A. Remley 1,3 , Joel Linden , Todd W. Bauer , Julien Dimastromatteo 2
1 Department of Surgery, University of Virginia, Charlottesville, VA 22903, USA.
2 Adovate, Charlottesville, VA 22901, USA.
3 University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22903, USA.
Correspondence to: Dr. Julien Dimastromatteo, Adovate, 1180 Seminole Tr. Ste 495, Charlottesville, VA 22901, USA. E-mail:
jdimastro@adovate.com
How to cite this article: Remley VA, Linden J, Bauer TW, Dimastromatteo J. Unlocking antitumor immunity with adenosine
receptor blockers. Cancer Drug Resist 2023;6:748-67. https://dx.doi.org/10.20517/cdr.2023.63

Received: 16 Jun 2023 First Decision: 18 Sep 2023 Revised: 6 Oct 2023 Accepted: 16 Oct 2023 Published: 25 Oct 2023
Academic Editor: Godefridus J. Peters Copy Editor: Pei-Yun Wang Production Editor: Pei-Yun Wang

Abstract
Tumors survive by creating a tumor microenvironment (TME) that suppresses antitumor immunity. The TME
suppresses the immune system by limiting antigen presentation, inhibiting lymphocyte and natural killer (NK) cell
activation, and facilitating T cell exhaustion. Checkpoint inhibitors like anti-PD-1 and anti-CTLA4
are immunostimulatory antibodies, and their blockade extends the survival of some but not all cancer
patients. Extracellular adenosine triphosphate (ATP) is abundant in inflamed tumors, and its metabolite,
adenosine (ADO), is a driver of immunosuppression mediated by adenosine A2A receptors (A2AR) and
adenosine A2B receptors (A2BR) found on tumor-associated lymphoid and myeloid cells. This review will
focus on adenosine as a key checkpoint inhibitor-like immunosuppressive player in the TME and how
reducing adenosine production or blocking A2AR and A2BR enhances antitumor immunity.

Keywords: Immunotherapy, adenosine, adenosine receptors, adenosine A2A receptors (A2AR), adenosine A2B
receptors (A2BR), tumor cells, immune cells, tumor microenvironment

INTRODUCTION
Deadly tumors have the ability to resist the body’s formidable immune defenses. They create protective
micro-environments that limit antigen presentation, inhibit T and natural killer (NK) cell responses, and

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0
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