The ectonucleotidase CD39 has been regarded as a promising immune checkpoint in solid tumors. However, the expression of CD39 by tumor-infiltrating CD8⁺ T cells as well as their potential roles and clinical implications in human gastric cancer (GC) remain largely unknown. Here, we found that GC-infiltrating CD8⁺ T cells contained a fraction of CD39^hi cells that constituted about 6.6% of total CD8⁺ T cells in tumors. These CD39^hi cells enriched for GC-infiltrating CD8⁺ T cells with features of exhaustion in transcriptional, phenotypic, metabolic and functional profiles. Additionally, GC-infiltrating CD39^hiCD8⁺ T cells were also identified for tumor-reactive T cells, as these cells expanded in vitro were able to recognize autologous tumor organoids and induced more tumor cell apoptosis than those of expanded their CD39^int and CD39^-CD8⁺ counterparts. Furthermore, CD39 enzymatic activity controlled GC-infiltrating CD39^hiCD8⁺ T cell effector function, and blockade of CD39 efficiently enhanced their production of cytokines IFN-γ and TNF-α. Finally, high percentages of GC-infiltrating CD39^hiCD8⁺ T cells correlated with tumor progression and independently predicted patients' poor overall survival. These findings provide novel insights into the association of CD39 expression level on CD8⁺ T cells with their features and potential clinical implications in GC, and empowering those exhausted tumor-reactive CD39^hiCD8⁺ T cells through CD39 inhibition to circumvent the suppressor program may be an attractive therapeutic strategy against GC.

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