The Clinical Significance of CD73 in Cancer - Review Overview

Sep 24, 2026

The review examines CD73 as an emerging treatment target in cancer immunotherapy, focusing on its role within purinergic signaling and the generation of immune-suppressive adenosine. Higher CD73 expression in tumors correlates with poor prognosis and contributes to suppression of anti-tumor immunity as well as tumor-promoting processes including proliferation, growth, angiogenesis, and metastasis. Upregulated CD73 and adenosine production support resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy, motivating CD73 inhibition to enhance therapeutic efficacy and combination strategies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages21

Reading Time53 min

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Abstract

Introduction

Tumor microenvironment and adenosine signalling

CD39/CD73 pathway and immune suppression

Figure 1. ATP and adenosine signalling in the tumour microenvironment

Review The Clinical Signiﬁcance of CD73 in Cancer Niklas Bach 1, Riekje Winzer 1, Eva Tolosa 1, Walter Fiedler 2, * and Franziska Brauneck 2,3 Citation: Bach, N.; Winzer, R.; Tolosa, E.; Fiedler, W.; Brauneck, F. The Clinical Signiﬁcance of CD73 in Cancer. Int. J. Mol. Sci. 2023, 24, 11759. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms241411759 Academic Editor: Donald J. Buchsbaum Received: 11 June 2023 Revised: 4 July 2023 Accepted: 10 July 2023 Published: 21 July 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; [7085323@stud.uke.uni-hamburg.de](7085323@stud.uke.uni-hamburg.de) (N.B.); [r.winzer@uke.de](r.winzer@uke.de) (R.W.); [e.tolosa@uke.de](e.tolosa@uke.de) (E.T.) 2 Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; [f.brauneck@uke.de](f.brauneck@uke.de) 3 Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany * Correspondence: ﬁedler@uke.de Abstract: The search for new and effective treatment targets for cancer immunotherapy is an ongoing challenge. Alongside the more established inhibitory immune checkpoints, a novel potential target is CD73 . As one of the key enzymes in the purinergic signalling pathway CD73 is responsible for the generation of immune suppressive adenosine. The expression of CD73 is higher in tumours than in the corresponding healthy tissues and associated with a poor prognosis. CD73, mainly by the production of adenosine, is critical in the suppression of an adequate anti-tumour immune response, but also in promoting cancer cell proliferation, tumour growth, angiogenesis, and metastasis. The upregulation of CD73 and generation of adenosine by tumour or tumour-associated immune cells is a common resistance mechanism to many cancer treatments such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Therefore, the inhibition of CD73 represents a new and promising approach to increase therapy efﬁcacy. Several CD73 inhibitors have already been developed and successfully demonstrated anti-cancer activity in preclinical studies. Currently, clinical studies evaluate CD73 inhibitors in different therapy combinations and tumour entities. The initial results suggest that inhibiting CD73 could be an effective option to augment anti-cancer immunotherapeutic strategies. This review provides an overview of the rationale behind the CD73 inhibition in different treatment combinations and the role of CD73 as a prognostic marker. Keywords: CD73; immunotherapeutic strategies; immune suppression; cancer 1. Introduction Immunotherapy marks a breakthrough in cancer therapy and has achieved impressive therapeutic effects [1] . Still, only 20–40% of patients respond, and the therapeutic effects are often short-lived due to the tumour's high capacity to adapt and to develop resistance mechanisms [2] . While combinations of different treatments and further checkpoint targets are under investigation, a deeper understanding of the tumour microenvironment (TME) is crucial for the development of new therapies. One component ofthe TME is the immunosuppressive metabolite adenosine. Tumours themselves and cancer therapies trigger the release of high amounts of ATP into extracellular compartments [3], which is then dephosphorylated by the ectonucleotidases CD39 and CD73 to produce adenosine [4] . The extracellular concentration of ad

FAQs

Why is CD73 considered an important target in cancer immunotherapy?

CD73 generates immune-suppressive adenosine in the purinergic signalling pathway. Tumors often show higher CD73 expression, which is linked to poor prognosis and suppression of effective anti-tumor immune responses.

How does adenosine produced by the CD39/CD73 pathway affect immune cells?

Adenosine engages A2A or A2B receptors on T cells, increasing cAMP and broadly suppressing T-cell functions. It also promotes pro-tumor phenotypes in dendritic cells and inhibits natural killer cell maturation and cytotoxic activity.

What role does CD73 play in treatment resistance?

Upregulation of CD73 and increased adenosine production by tumor or tumor-associated immune cells constitute a common resistance mechanism across chemotherapy, radiotherapy, targeted therapy, and immunotherapy.

Sep 24, 2026

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