{"doi":"10.1126/sciimmunol.adi4191","title":"A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression","abstract":"Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8 + T cell activation and suppressed melanoma progression. CD63 + mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63 + mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.","journal":"Science Immunology","year":2024,"id":416536,"datarank":0.7289718606542509,"base_score":4.859812404361672,"endowment":4.859812404361672,"self_citation_contribution":0.7289718606542509,"citation_network_contribution":0.0,"self_endowment_contribution":0.7289718606542509,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":128,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9407,"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":1148467,"name":"Yue Xue","orcid":"0009-0004-2141-2044","position":1,"is_corresponding":false},{"id":862164,"name":"Y‐Van Nguyen","orcid":"0000-0003-1888-2147","position":2,"is_corresponding":false},{"id":239524,"name":"Nicholas C. DeVito","orcid":"0000-0001-7537-8647","position":3,"is_corresponding":false},{"id":1200888,"name":"X F Wang","orcid":"0009-0007-5226-5632","position":4,"is_corresponding":false},{"id":239531,"name":"Alisha Holtzhausen","orcid":"0000-0003-3604-7401","position":5,"is_corresponding":false},{"id":32895,"name":"Georgia M. Beasley","orcid":"0000-0001-6387-9030","position":6,"is_corresponding":false},{"id":727465,"name":"Balamayooran Theivanthiran","orcid":"0000-0003-4816-199X","position":7,"is_corresponding":false},{"id":239532,"name":"Brent A. Hanks","orcid":"0000-0002-2803-3272","position":8,"is_corresponding":false},{"id":239525,"name":"Michael P. Plebanek","orcid":"0000-0002-4966-5199","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:56:44.873714Z","pmid":"38728412","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":[]}