Tumor Exosomal ENPP1 Hydrolyzes cGAMP to Inhibit cGAS‐STING Signaling

Abstract To evade immune surveillance, tumor cells express ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) on the surface of their membrane, which degrades extracellular cyclic GMP‐AMP (cGAMP), thereby inhibiting the cyclic GMP‐AMP synthase (cGAS) stimulator of interferon gene (STING) DNA‐sensing pathway. To fully understand this tumor stealth mechanism, it is essential to determine whether other forms of ENPP1 with hydrolytic cGAMP activity also are present in the tumor microenvironment to regulate this innate immune pathway. Herein, it is reported that various tumor‐derived exosomes carry ENPP1, and can hydrolyze synthetic 2′3′‐cGAMP and endogenous 2′3′‐cGAMP produced by cells to inhibit cGAS‐STING pathway in immune cells. Moreover, tumor exosomal ENPP1 also can hydrolyze 2′3′‐cGAMP bound to LL‐37 (an effective transporter of 2′3′‐cGAMP) to inhibit STING signaling. Furthermore, high expression of ENPP1 in exosomes is observed isolated from human breast and lung cancer tissue, and tumor exosomal ENPP1 inhibited the immune infiltration of CD8+ T cells and CD4+ T cells. The results elucidate the essential function of tumor exosomal ENPP1 in the cGAS‐STING pathway, furthering understanding of the crosstalk between the tumor cells and immune system.