ENPP1 expression correlates with poor prognosis in many
cancers, and we previously discovered that ENPP1 is the dominant
hydrolase of extracellular
cGAMP: a
cancer-cell-produced immunotransmitter that activates the anticancer
STING pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single cell
RNA-seq (
scRNA-seq), we show that ENPP1 overexpression drives primary
breast tumor growth and
metastasis by synergistically dampening extracellular
cGAMP-
STING mediated antitumoral immunity and activating immunosuppressive extracellular
adenosine (eADO) signaling. In addition to
cancer cells, stromal and immune cells in the tumor microenvironment (TME) also express ENPP1 that restrains their response to
tumor-derived
cGAMP. Enpp1 loss-of-function in both
cancer cells and normal tissues slowed primary
tumor initiation and growth and prevented
metastasis in an extracellular
cGAMP- and
STING-dependent manner. Selectively abolishing the
cGAMP hydrolysis activity of ENPP1 phenocopied total ENPP1 knockout, demonstrating that restoration of paracrine
cGAMP-
STING signaling is the dominant anti-
cancer mechanism of ENPP1 inhibition. Strikingly, we find that
breast cancer patients with low ENPP1 expression have significantly higher immune infiltration and improved response to
therapeutics impacting
cancer immunity upstream or downstream of the
cGAMP-
STING pathway, like
PARP inhibitors and anti-PD1. Altogether, selective inhibition of ENPP1's
cGAMP hydrolase activity alleviates an innate immune checkpoint to boost
cancer immunity and is therefore a promising therapeutic approach against
breast cancer that may synergize with other
cancer immunotherapies.