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-A2a/A2b 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 A2a/A2b receptors in regulating radiosensitivity. Therapeutic studies evaluated combinatorial targeting of CD73 and A2a/A2b 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 A2a/A2b 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 PD1 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-A2a/A2b axis in combination with radiotherapy and checkpoint blockade represents a rational strategy to overcome radioresistance and improve antitumor immunity.
Bansal, S., Aparicio, L., Krishnan, A., Liu, C., Caprio, L., Chiarella, A., Sarti, S., Piersant, J., Rahiman, C., An, J., Mccann, P., Sen, N., Ragaishis, B., Derakhshan, F., Taback, B., Rustgi, A., Izar, B., Spina, C.
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