Targeting CD73-A 2a R-Mediated Adenosine Signaling at the Tumor-Immune Interface Overcomes Radioresistance
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Radiotherapy efficacy is constrained by an immunosuppressive tumor microenvironment (TME) enriched in extracellular adenosine and suppressive myeloid populations that attenuate cytotoxic T-cell responses. The CD73–adenosine–A 2a /A 2b receptor axis represents a key metabolic immune checkpoint; however, the relative contributions of tumor cell–intrinsic versus host-derived adenosine signaling to radiotherapy response remain incompletely defined.
Methods
Using orthotopic murine breast carcinoma models, we interrogated radiation-induced adenosine dynamics and downstream immune remodeling through quantitative adenosine measurements, bulk RNA sequencing, and multiparameter flow cytometry. Genetically engineered models were employed to dissect the roles of tumor-derived CD73 and host A 2a /A 2b receptors in regulating radiosensitivity. Therapeutic studies evaluated combinatorial targeting of CD73 and A 2a /A 2b receptors with radiotherapy and anti–PD-1, followed by comprehensive immune profiling in breast carcinomas.
Results
Tumor cell–intrinsic CD73 and host A2A receptor signaling cooperatively drive radioresistance and tumor progression. Radiotherapy induces a rapid surge in intratumoral adenosine, triggering transcriptional and cellular programs consistent with myeloid-mediated immunosuppression and lymphocyte dysfunction. Although T-cell infiltration increases at later time point post-irradiation, effector function remains constrained. Pharmacologic inhibition of CD73 and A 2a /A 2b receptors partially restores T-cell functionality but is insufficient for durable tumor control as monotherapy. In contrast, concurrent blockade of adenosine signaling during radiotherapy, followed by adjuvant PD-1 inhibition, amplifies adaptive antitumor immunity and significantly enhances tumor control.
Conclusions
These findings define a mechanistic link between radiation-induced adenosine signaling and immune dysfunction in the TME. Targeting the CD73–A 2a /A 2b axis in combination with radiotherapy and checkpoint blockade represents a rational strategy to overcome radioresistance and improve antitumor immunity.
STATEMENT OF SIGNIFICANCE
The tumor and immune cell contributions to adenosine signaling play a central role in shaping the therapeutic outcomes of tumor irradiation. Therapeutic targeting of the adenosine signaling axis improves radiosensitivity and efficacy of checkpoint blockade.
