{"doi":"10.1101/2025.06.27.661921","title":"PD-L1 ligation on NK cells induces a metabolic shift from glycolysis to fatty acid oxidation, enhancing tumor infiltration and control","abstract":"Abstract PD-L1 blockade benefits even PD-L1-negative tumors, suggesting that non-tumor cells contribute to PD-L1 expression. Natural killer (NK) cells, vital mediators of innate immunity, vigorously express PD-L1 upon activation. We demonstrate that the ligation of PD-L1 on circulating and tumor-infiltrating NK cells with the therapeutic anti-PD-L1 antibody atezolizumab, soluble PD-1, or PD-1+ cells enhances NK cell-mediated tumor clearance via changes in metabolism, adhesion, and migration. PD-L1 engagement increases NK cell tumor infiltration via the CXCR3 pathway and cytoskeletal remodeling, supported by a metabolic shift from glycolysis to fatty acid oxidation (FAO). Loss of a key FAO enzyme, CPT1A, in NK cells abrogates the PD-L1-mediated anti-tumor effect, supporting a critical role for FAO in enhanced NK cell killing. The PD-L1-triggered shift away from glycolysis permits NK cells to remain highly effective at tumor killing in glucose-restricted TME. Taken together, PD-L1 ligation enhances NK cell cytotoxicity and tumor infiltration and contributes to NK resilience in challenging TME conditions, resulting in a more effective anti-tumor immunity. One sentence summary PD-L1 engagement on NK cells enhances their tumor infiltration and cytotoxic activity by inducing a metabolic switch from glycolysis to fatty acid oxidation, enabling sustained function in the glucose-deprived tumor microenvironment.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558388,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9613,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":684553,"name":"Kyle B. Lupo","orcid":"0000-0003-3442-0647","position":1,"is_corresponding":false},{"id":749866,"name":"Rosa Sottile","orcid":"0000-0003-2950-9508","position":2,"is_corresponding":false},{"id":1458820,"name":"Gianluca Scarno","orcid":"0000-0002-2183-5942","position":3,"is_corresponding":false},{"id":1333700,"name":"Clara Lawry","orcid":null,"position":4,"is_corresponding":false},{"id":1333701,"name":"Gabryelle Kolk","orcid":null,"position":5,"is_corresponding":false},{"id":352732,"name":"Brian C. Shaffer","orcid":"0000-0003-3433-9179","position":6,"is_corresponding":false},{"id":291699,"name":"Snehal G. Patel","orcid":"0000-0001-9775-5132","position":7,"is_corresponding":false},{"id":977324,"name":"Ahmed Al‐Niaimi","orcid":"0000-0001-9767-6274","position":8,"is_corresponding":false},{"id":322860,"name":"Colleen M. Lau","orcid":"0000-0001-7538-094X","position":9,"is_corresponding":false},{"id":61584,"name":"Joseph C. Sun","orcid":"0000-0001-8062-9033","position":10,"is_corresponding":false},{"id":320883,"name":"Katharine C. Hsu","orcid":"0000-0003-2827-5324","position":11,"is_corresponding":false},{"id":570043,"name":"Katja Srpan","orcid":"0000-0003-4830-3230","position":0,"is_corresponding":true}],"reference_count":115,"raw_metadata":null,"created_at":"2026-07-19T02:55:25.969263Z","pmid":null,"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":[]}