CD39 on CD8+ Tumour-Infiltrating Lymphocytes: A Paradoxical Marker of Tumour Reactivity and Immunosuppression.

CD39 (ENTPD1) occupies a paradoxical position in the immunology of solid tumours. On CD8+ tumour-infiltrating lymphocytes (TILs), its surface expression serves as one of the most reliable available markers of genuine tumour-antigen experience and identifies the clonally expanded tissue-resident and cytolytically competent T cells, that are largely absent from the bystander populations, which are specific for tumour-unrelated antigens and numerically dominate many tumour infiltrates. Yet the same enzymatic activity that defines CD39, the hydrolysis of extracellular ATP (eATP) to AMP, directly feeds CD73-dependent adenosine generation. These very cells therefore actively perpetuate the immunosuppressive purinergic milieu that constrains their own effector function and that of surrounding immune cells. CD39+CD8+ TILs thus represent simultaneously the best cellular evidence that a productive anti-tumour immune response has occurred, and among the most potent local drivers of its suppression. This review places this paradox at its centre, dissecting the molecular basis of CD39 expression, its two opposing functional identities across solid tumour types and the therapeutic logic that follows: Blocking CD39 activity could simultaneously release the suppressive brake and preserve the tumour-reactive cells that express it.