{"doi":"10.1016/j.celrep.2024.114209","title":"Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint","abstract":"2'3'-Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) is a second messenger synthesized upon detection of cytosolic double-stranded DNA (dsDNA) and passed between cells to facilitate downstream immune signaling. Ectonucleotide pyrophosphatase phosphodiesterase I (ENPP1), an extracellular enzyme, was the only metazoan hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and likely the only other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from ENPP1's and accounts for all cGAMP hydrolysis activity in ENPP1-deficient mice. Importantly, we also show that, as with ENPP1, selectively abolishing ENPP3's cGAMP hydrolysis activity results in diminished cancer growth and metastasis of certain tumor types in a stimulator of interferon genes (STING)-dependent manner. Both ENPP1 and ENPP3 are extracellular enzymes, suggesting the dominant role that extracellular cGAMP must play as a mediator of cell-cell innate immune communication. Our work demonstrates that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a target for cancer immunotherapy.","journal":"Cell Reports","year":2024,"id":419917,"datarank":0.5495342469194471,"base_score":3.6635616461296463,"endowment":3.6635616461296463,"self_citation_contribution":0.5495342469194471,"citation_network_contribution":0.0,"self_endowment_contribution":0.5495342469194471,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":38,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":494034,"name":"Songnan Wang","orcid":"0000-0002-4276-2965","position":1,"is_corresponding":false},{"id":232616,"name":"Jacqueline A. Carozza","orcid":"0000-0001-6068-2259","position":2,"is_corresponding":false},{"id":709663,"name":"Bahar Zirak","orcid":null,"position":3,"is_corresponding":false},{"id":664982,"name":"Vishvak Subramanyam","orcid":"0000-0002-6144-8322","position":4,"is_corresponding":false},{"id":1047538,"name":"Gita C. Abhiraman","orcid":"0000-0002-0546-4133","position":5,"is_corresponding":false},{"id":766528,"name":"Xuchao Lyu","orcid":null,"position":6,"is_corresponding":false},{"id":43301,"name":"Hani Goodarzi","orcid":"0000-0002-9648-8949","position":7,"is_corresponding":false},{"id":232622,"name":"Lingyin Li","orcid":"0000-0003-4386-7926","position":8,"is_corresponding":false},{"id":1210636,"name":"Rachel Mardjuki","orcid":null,"position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:57:19.937291Z","pmid":"38749434","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}