Entpd1, also known as CD39, is an ectonucleotidase that plays a crucial role in the conversion of ADP/ATP to AMP as part of the CD39-CD73-adenosine pathway [1,2,3]. This pathway is important in calibrating purinergic signals to immune cells, shifting the environment from pro-inflammatory (ATP-driven) to anti-inflammatory (adenosine-induced) [2].

In cancer, Entpd1 expressed on regulatory T cells (Tregs) inhibits effector lymphocytes, creating a favorable environment for tumor growth. Knockout models and surrogate inhibitors of CD39 support the anticancer activity of CD39 inhibition, predicting a good safety profile for inhibitory compounds [1]. In hepatic metastatic cancer mouse models, Cd39 null vasculature or Cd39 null bone marrow-derived cells strongly inhibited tumor growth, indicating that CD39 expression on Tregs promotes metastatic growth [5]. In septic CD39 -/- mice, there were higher levels of inflammatory cytokines and more pronounced liver injury compared to wild-type mice, suggesting CD39 attenuates sepsis-associated liver injury [4].

In conclusion, Entpd1 is essential in regulating the immune environment through the CD39-CD73-adenosine pathway. Gene knockout mouse models have been instrumental in revealing its role in cancer and sepsis-related liver injury, highlighting its potential as a therapeutic target in oncology and for managing sepsis-induced hepatic damage.