Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS–STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti–PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. Significance: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells. This article is highlighted in the In This Issue feature, p. 995

amplification is present in a minority of acral lentiginous and mucosal melanomas. Activating mutations in were identified in nonuveal melanoma subtypes and are frequently comutated with canonical drivers. HER2 could represent a therapeutically relevant target across melanoma subtypes.

Background Multiplex polymerase chain reaction (PCR) panels allow for rapid detection or exclusion of pathogens causing meningitis and encephalitis (ME). The clinical impact of rapid multiplex PCR ME panel results on the duration of empiric antibiotic therapy is not well characterized. Methods We performed a retrospective pre-post study at our institution that evaluated the clinical impact of a multiplex PCR ME panel among adults with suspected bacterial meningitis who received empiric antibiotic therapy and underwent lumbar puncture in the emergency department. The primary outcome was the duration of empiric antibiotic therapy. Results The positive pathogen detection rates were similar between pre- and post-multiplex PCR ME panel periods (17.5%, 24 of 137, vs. 20.3%, 14 of 69, respectively). The median duration of empiric antibiotic therapy was significantly reduced in the post-multiplex PCR ME panel period compared to the pre-multiplex PCR ME panel period (34.7 h vs. 12.3 h, P=0.01). At any point in time, 46% more patients in the post-multiplex PCR ME panel period had empiric antibiotic therapy discontinued or de-escalated compared to the pre-multiplex PCR ME panel period (sex- and immunosuppressant use-adjusted HR 1.46, P=0.01). The median hospital length of stay was shorter in the post-multiplex PCR ME panel period (3 d vs. 4 d, P=0.03). Conclusions The implementation of the multiplex PCR ME panel for bacterial meningitis reduced the duration of empiric antibiotic therapy and possibly hospital length of stay compared to traditional microbiological testing methods.