The ATP-adenosine pathway functions as a key modulator of innate and adaptive immunity within the tumor microenvironment, and cancer immune evasion largely involves the generation of high amounts of immunosuppressive extracellular adenosine (eADO). Consequently, inhibition of eADO-generating enzymes and/or eADO receptors can effectively restore the antitumor immunity of multiple immune cells. With several clinical strategies currently being explored to modulating the eADO pathway in patients with cancer, recent clinical data with antagonists targeting CD73 and A2A receptor have demonstrated a promising therapeutic potential in cancer. Recent findings reveal that the ectonucleotidase CD39, the limiting enzyme been viewed as “immunological switch”, converts ATP-driven pro-inflammatory milieu to an anti-inflammatory state mediated by adenosine. Owing to its superior feature of CD39 antagonism that rely not only on preventing the accumulation of adenosine but also on the stabilization of extracellular ATP to restore antitumor immunity, several inhibitors and clinical trials based on CD39 are being evaluated. Consequently, there is currently a focus on understanding the role of CD39 in governing immunity and how therapeutic strategies targeting this pathway alter the antitumor potential. We herein review the impact of CD39 on tumor microenvironment with a focus on treatment preference. Additionally, we also discuss the implication for rational combination therapies, molecular regulation, as well as potential limitations.
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