Adenosinergic signaling as a target for natural killer cell immunotherapy

Purinergic signaling through adenosine plays a key role in immune regulation. Hypoxia-driven accumulation of extracellular adenosine results in the generation of an immunosuppressive niche that fuels tumor development. Such immunometabolic modulation has shown to be a promising therapeutic target through blockade of adenosine receptors which mediate adenosine's immunosuppressive function, or cancer-associated ectonucleotidases CD39 and CD73 that catalyze the synthesis of adenosine. Adenosinergic signaling heavily implicates natural killer cells through both direct and indirect effects on their cytolytic activity, expression of cytotoxic granules, interferon-γ, and activating receptors. Continuing work has uncovered multiple checkpoints linked to adenosine within the purinergic signaling cascade as contributing to immune evasion from NK cell effector function. Here, we discuss these checkpoints and the recent body of work that focuses on adenosinergic signaling as a target for natural killer cell of cancer.