Immune Receptor A2AR Plays Paradoxical Dual Role in T-Cell Exhaustion, Challenging Checkpoint Therapy Assumptions

A new Northwestern Medicine study has upended the conventional understanding of the adenosine A2A receptor (A2AR) (搜索)搜索该靶点, revealing that this key immunoregulatory molecule plays a paradoxical dual role in promoting CD8+ T-cell exhaustion during chronic infection and cancer. The findings, published in the Proceedings of the National Academy of Sciences, challenge the prevailing view of A2AR as a purely linear immunosuppressive checkpoint and may explain why A2AR-targeted cancer therapies have disappointed in recent clinical trials.

"This discovery really challenges the traditional view of this emerging immune checkpoint molecule, the A2A receptor, as a purely linear immunosuppressive checkpoint. It actually uncovers a complex context-dependent dynamic where too much or too little receptor activity drives T-cells towards a terminal dysfunctional state over time," said Bin Zhang, MD, PhD, the Johanna Dobe Professor of Cancer Immunology and senior author of the study. Zhang is also a professor of Medicine in the Division of Hematology and Oncology, of Microbiology-Immunology and of Pathology.

A Surprising Mechanism of T-Cell Dysfunction

CD8+ T-cells are a pillar of the body's adaptive immune response, patrolling for pathogens and leading tumor surveillance. During chronic viral infection and cancer, these cells undergo sustained T-cell receptor stimulation and inflammatory stress, which over time contributes to T-cell exhaustion — a state of progressive functional decline.

The A2A receptor has long been understood as an "immunosuppressive brake" that suppresses T-cell function in response to elevated levels of the signaling molecule adenosine in inflamed or hypoxic tumor microenvironments. This understanding drove the development of A2AR-targeted therapies, which have been tested in clinical trials for several cancers.

However, these therapies have shown limited efficacy, including in metastatic castration-resistant prostate cancer (搜索)搜索该疾病 and renal cell carcinoma (搜索)搜索该疾病. Zhang's team set out to better understand A2AR's role in CD8+ T-cell differentiation and cell fate decisions — and what they found was unexpected.

Dual Pathways to Exhaustion

Using single-cell multiomics profiling, the researchers discovered that both sustained A2AR expression and the loss of A2AR independently drive CD8+ T-cells to terminal exhaustion through distinct signaling pathways. Specifically, they found that A2AR deficiency activates CD122 (搜索)搜索该靶点 protein–dependent signaling to drive T-cell exhaustion.

In a critical experiment, the team demonstrated that genetically deleting the CD122 (搜索)搜索该靶点 protein in A2AR-deficient CD8+ T-cells in mouse models reduced terminal exhaustion. This finding positions CD122 signaling as a key mediator of A2AR loss–driven exhaustion and reveals a previously unrecognized complexity in how this receptor shapes T-cell fate.

Implications for Future Therapeutic Strategies

The findings highlight the need for new therapeutic strategies that fine-tune, rather than merely inhibit, immune regulatory pathways to improve treatment outcomes. "We hope this has a huge impact in that we can reconsider A2AR blockade strategies to improve the design of clinical trials. That's something we're really looking forward to in the next stage of this work," Zhang said.

Weiguo Cui, PhD, professor of Pathology in the Division of Experimental Pathology, served as co-corresponding author of the study. Both Cui and Zhang are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University查看公司主页 and the Center for Human Immunobiology.

The work was supported in part by National Institutes of Health grants CA290743, CA258857, AI148403 and CA290743; the Melanoma Research Alliance (MRA) Next Steps Grant; and an Established Scholar Award.