{"doi":"10.1158/2159-8290.cd-22-1301","title":"Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade","abstract":"The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for enhanced tumor control. Our data demonstrate that formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T-cell function. SIGNIFICANCE: This study identifies that deficiencies in 1C metabolism limit the efficacy of PD-1 blockade in B16-OVA tumors. Supplementing 1C metabolism with formate during anti-PD-1 therapy enhances CD8+ T-cell fitness in the TME and CD8+ T-cell-mediated tumor clearance. These findings demonstrate that formate supplementation can enhance exhausted CD8+ T-cell function. See related commentary by Lin et al., p. 2507. This article is featured in Selected Articles from This Issue, p. 2489.","journal":"Cancer Discovery","year":2023,"id":319961,"datarank":0.5955437870328184,"base_score":3.970291913552122,"endowment":3.970291913552122,"self_citation_contribution":0.5955437870328184,"citation_network_contribution":0.0,"self_endowment_contribution":0.5955437870328184,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":52,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"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":574896,"name":"Ilaria Elia","orcid":"0000-0003-0922-9429","position":1,"is_corresponding":false},{"id":267959,"name":"Osmaan Shahid","orcid":"0000-0002-3694-8480","position":2,"is_corresponding":false},{"id":35829,"name":"Emily F. Gaudiano","orcid":"0000-0001-9523-1183","position":3,"is_corresponding":false},{"id":1029821,"name":"Natalia E. Sifnugel","orcid":"0009-0004-0608-5305","position":4,"is_corresponding":false},{"id":745803,"name":"Sheila Johnson","orcid":"0000-0001-5062-7934","position":5,"is_corresponding":false},{"id":1029822,"name":"Amy G. Reynolds","orcid":"0009-0000-2935-1750","position":6,"is_corresponding":false},{"id":267964,"name":"Megan E. Fung","orcid":"0000-0002-9053-0915","position":7,"is_corresponding":false},{"id":108666,"name":"Shakchhi Joshi","orcid":"0000-0002-3120-7659","position":8,"is_corresponding":false},{"id":108670,"name":"Martin W. LaFleur","orcid":"0000-0002-5017-774X","position":9,"is_corresponding":false},{"id":1016291,"name":"Joon Seok Park","orcid":"0000-0003-4001-6886","position":10,"is_corresponding":false},{"id":61817,"name":"Kristen E. Pauken","orcid":"0000-0002-4309-7880","position":11,"is_corresponding":false},{"id":108672,"name":"Joshua D. Rabinowitz","orcid":"0000-0002-1247-4727","position":12,"is_corresponding":false},{"id":4539,"name":"Gordon J. Freeman","orcid":"0000-0002-7210-5616","position":13,"is_corresponding":false},{"id":6945,"name":"Marcia C. Haigis","orcid":"0000-0003-2530-2681","position":14,"is_corresponding":false},{"id":4542,"name":"Arlene H. Sharpe","orcid":"0000-0002-9736-2109","position":15,"is_corresponding":false},{"id":391315,"name":"Jared H. Rowe","orcid":"0000-0002-4223-4433","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:07:17.361058Z","pmid":"37728660","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":[]}