In our study, we investigated the role of CD39 on tumor‐infiltrating CD8⁺ T lymphocytes (CD8⁺ TILs) in colorectal, head and neck and pancreatic cancers. Partially confirming recent observations correlating the CD39 expression with T‐cell exhaustion, we demonstrated a divergent functional activity in CD39⁺CD8⁺ TILs. On the one hand, CD39⁺CD8⁺ TILs (as compared to their CD39⁻ counterparts) produced significantly lower IFN‐γ and IL‐2 amounts, expressed higher PD‐1, and inversely correlated with perforin and granzyme B expression. On the other, they displayed a significantly higher proliferative capacity ex vivo that was inversely correlated with the PD‐1 expression. Therefore, CD39⁺CD8⁺ TILs, including those co‐expressing the CD103 (a marker of T resident memory [TRM] cells), were defined as partially dysfunctional T cells that correlate with tumor patients with initial progression stages. Interestingly, our results identified for the first time a single nucleotide polymorphism (SNP rs10748643 A>G), as a genetic factor associated with CD39 expression in CD8⁺ TILs. Finally, we demonstrated that compounds inhibiting CD39‐related ATPases improved CD39⁺CD8⁺ T‐cell effector function ex vivo, and that CD39⁺CD8⁺ TILs displayed effective suppression function in vitro. Overall these data suggest that the SNP analysis may represent a suitable predictor of CD39⁺CD8⁺ T‐cell expression in cancer patients, and propose the modulation of CD39 as a new strategy to restore partially exhausted CD8⁺ TILs.