The prognostic significance of adenosine pathway biomarkers CD73 and adenosine 2A receptor in non-small cell lung cancer

Blocking the adenosine signaling pathway may enhance anti-tumor immunity. This study evaluates the prognostic significance of adenosine pathway markers in non-small cell lung cancer (NSCLC). In the research, adenosine pathway related biomarkers including CD73, CD39, adenosine 2 A receptor (A2AR) and immune-related markers were analyzed via immunohistochemistry in 158 NSCLC tissues (stage I/III adenocarcinoma and squamous cell carcinoma). Prognostic differences were validated using The Cancer Genome Atlas data. Gene mutation frequencies and functional enrichment were assessed in subgroups stratified by CD73 expression. The results showed that CD73 expression on tumor cells was higher in adenocarcinoma versus squamous cell carcinoma ( p < 0.001), while CD73 on immune cells was elevated in squamous carcinoma ( p = 0.001). A2AR expression on tumor cells correlated with male sex ( p < 0.001), smoking history ( p = 0.001), and squamous histology ( p = 0.002). High CD73 expression on tumor cells independently predicted poor disease-free survival (DFS) (HR = 2.12, 95% CI: 1.16–3.89; p = 0.01), validated in TCGA (log-rank p < 0.05 for OS and DFS). Mutation frequencies of KRAS and EGFR were higher in CD73-high tumors ( p < 0.01), while NFE2L2 and EP300 mutations were reduced ( p < 0.001). These genes were enriched in the FoxO signaling pathway (FDR < 0.05). In conclusion, high CD73 expression on tumor cells is an independent prognostic risk factor in NSCLC, associated with distinct genetic alterations. Targeting the adenosine pathway may offer therapeutic potential in CD73-high subgroups. Registry and the Registration No. of the study/trial: N/A.