{"doi":"10.1126/sciadv.adk1853","title":"DGKα/ζ inhibition lowers the TCR affinity threshold and potentiates antitumor immunity","abstract":"Diacylglycerol kinases (DGKs) attenuate diacylglycerol (DAG) signaling by converting DAG to phosphatidic acid, thereby suppressing pathways downstream of T cell receptor signaling. Using a dual DGKα/ζ inhibitor (DGKi), tumor-specific CD8 T cells with different affinities (TRP1 high and TRP1 low ), and altered peptide ligands, we demonstrate that inhibition of DGKα/ζ can lower the signaling threshold for T cell priming. TRP1 high and TRP1 low CD8 T cells produced more effector cytokines in the presence of cognate antigen and DGKi. Effector TRP1 high - and TRP1 low -mediated cytolysis of tumor cells with low antigen load required antigen recognition, was mediated by interferon-γ, and augmented by DGKi. Adoptive T cell transfer into mice bearing pancreatic or melanoma tumors synergized with single-agent DGKi or DGKi and antiprogrammed cell death protein 1 (PD-1), with increased expansion of low-affinity T cells and increased cytokine production observed in tumors of treated mice. Collectively, our findings highlight DGKα/ζ as therapeutic targets for augmenting tumor-specific CD8 T cell function.","journal":"Science Advances","year":2023,"id":334146,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9478,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":854381,"name":"Elisa Bello","orcid":"0000-0001-7695-2567","position":1,"is_corresponding":false},{"id":1063104,"name":"Courtney T.S. Kureshi","orcid":null,"position":2,"is_corresponding":false},{"id":418766,"name":"Michael J. Walsh","orcid":"0000-0002-1283-6847","position":3,"is_corresponding":false},{"id":1062524,"name":"Victoria Lippert","orcid":"0009-0006-3883-2007","position":4,"is_corresponding":false},{"id":476728,"name":"Megan T. Hoffman","orcid":"0000-0003-0907-9977","position":5,"is_corresponding":false},{"id":50969,"name":"Michael Dougan","orcid":"0000-0001-9266-2009","position":6,"is_corresponding":false},{"id":715799,"name":"Tyler A. Longmire","orcid":"0000-0002-1621-1895","position":7,"is_corresponding":false},{"id":470013,"name":"Michael Wichroski","orcid":"0009-0009-2664-2347","position":8,"is_corresponding":false},{"id":227527,"name":"Stephanie K. Dougan","orcid":"0000-0002-2263-363X","position":9,"is_corresponding":false},{"id":530307,"name":"Rakeeb Kureshi","orcid":"0000-0003-2769-2468","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-19T01:09:48.843291Z","pmid":"38000024","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":[]}