ENPP1 Immunobiology as a Therapeutic Target

ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase) participates in the hydrolysis of different purine nucleotides in an array of physiologic processes. However, ENPP1 is frequently overexpressed in local relapses and tumor metastases, which are associated with poor prognosis and survival in a range of solid tumors. ENPP1 promotes an immunosuppressive tumor micro-environment (TME) by tilting the balance of ATP /adenosine (Ado) in conjunction with other components (CD38, CD39/ ENTPD1, and CD73/NT5E). Moreover, ENPP1 intersects with the stimulator of interferon genes (STING), impairing its robust immune response through the hydrolysis of the effector 2,⠁3 ⠁- cyclic GMP-AMP. Thus, ENPP1 blockade emerges as a unique target eliciting immune remodeling and leveraging the STING pathway. Several ENPP1 inhibitors have shown an immunostimu- latory effect, and their combination with other therapeutic modal- ities, such as immune-checkpoint blockade, STING activation, DNA damage response (DDR) inhibitors, and radiotherapy (RT), represents a promising avenue to boost antitumor-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.

Automated summary

ENPP1 is frequently overexpressed in local relapses and tumor metastases, promoting an immunosuppressive tumor micro-environment and impairing immune response. Blocking ENPP1 could enhance immune remodeling and activate the STING pathway. Combination therapy with ENPP1 inhibitors and other modalities shows potential in improving antitumor-immune responses and clinical outcomes. This review summarizes the current state of the art and provides new perspectives for novel treatment strategies.