ENPP1 Immunobiology as a Therapeutic Target.

ENPP1 (Ecto-nucleotide pyrophosphatase/ phosphodiesterase) participates in the hydrolysis of different purine nucleotides in an array of physiological processes. However, ENPP1 is frequently overexpressed in local relapses, and tumor metastases, which associates with poor prognosis and survival in a range of solid tumors. ENPP1 promotes an immunosuppressive tumor microenvironment (TME) by tilting the balance of ATP/Adenosine (Ado) in conjunction with other components (CD38, CD39/ENTPD1 and CD73/NT5E). Moreover, ENPP1 intersects the stimulator of interferon genes (STING), impairing its robust immune response through the hydrolysis of the effector 2´,3´-cyclic-GMP-AMP (cGAMP). Thus, ENPP1 blockade emerges as a unique target eliciting immune remodeling and leveraging the STING pathway. Several ENPP1 inhibitors have shown an immunostimulatory effect and their combination with other therapeutic modalities such as immune checkpoint blockade (ICB), STING activation, DNA damage response (DDR) inhibitors and radiotherapy (RT), represents a promising avenue to boost anti-tumor immune responses and to improve current clinical outcomes in several tumors. This comprehensive review summarizes the current state-of-the art and opens new perspectives for novel treatment strategies.