{"doi":"10.1158/2159-8290.cd-24-1232","title":"Tumor-associated NK Cells Regulate Distinct CD8+ T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers","abstract":"Immune checkpoint blockers (ICB) targeting the PD-1/PD-L1 axis represent established therapies for many cancers. However, resistance occurs in most patients due to complex immune-suppressive mechanisms in the tumor microenvironment. NK cells can play effector roles in tumor control, but their impact on T-cell dysfunction and ICB efficacy remains controversial. Through genetic and antibody-mediated NK cell depletion, we found that a subset of tumor-associated NK cells plays a negative role in ICB sensitivity; they further impede CD8+ T-cell differentiation toward a CD69+ BCL2+ EOMES+ GZMB+ TIM3- GITR- phenotype. Mechanistically, the retinoic acid receptor α-dependent differentiation program in CD8+ T cells is hindered by tumor-infiltrating NK cells via competition for IFNα and IL-2. Finally, we observed that lower frequencies of NK cells correlate with better clinical responses to ICBs in patients with cancer. These findings suggest potential avenues for enhancing CD8+ T cell-centered immunotherapy by targeting regulatory NK cells. SIGNIFICANCE: Although NK cells are traditionally viewed as antitumor effectors, our study uncovers their unexpected suppressive role in CD8+ T cell-based immunotherapy. By competing for cytokines, they disrupt retinoic acid receptor α-driven CD8+ T-cell differentiation and limit ICB efficacy. Clinically, reduced NK cell presence is associated with an enhanced immunotherapy response. See related commentary by Galvez-Cancino et al., p. 1777 See related article by Pozniak et al., p. 1819.","journal":"Cancer Discovery","year":2025,"id":510836,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"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":1309592,"name":"Juan Xie","orcid":"0000-0002-4170-9273","position":1,"is_corresponding":false},{"id":1265939,"name":"Kyeong Joo Jung","orcid":"0000-0002-0582-1583","position":2,"is_corresponding":false},{"id":573543,"name":"Yi Wang","orcid":"0000-0002-4046-9511","position":3,"is_corresponding":false},{"id":305216,"name":"Joanna Poźniak","orcid":"0000-0001-5739-1098","position":4,"is_corresponding":false},{"id":1367987,"name":"Niccolò Roda","orcid":"0000-0003-2798-2035","position":5,"is_corresponding":false},{"id":65650,"name":"Jean‐Christophe Marine","orcid":"0000-0003-2433-9837","position":6,"is_corresponding":false},{"id":270305,"name":"Brian Riesenberg","orcid":"0000-0001-7358-3479","position":7,"is_corresponding":false},{"id":1096011,"name":"Hyeongseon Jeon","orcid":"0000-0002-3539-4332","position":8,"is_corresponding":false},{"id":235824,"name":"Anjun Ma","orcid":"0000-0001-6269-398X","position":9,"is_corresponding":false},{"id":1367988,"name":"Nigel Cox","orcid":"0000-0001-6778-8339","position":10,"is_corresponding":false},{"id":267501,"name":"Darren Wethington","orcid":"0000-0002-3170-8998","position":11,"is_corresponding":false},{"id":815050,"name":"Kelsi Reynolds","orcid":"0009-0001-8201-7644","position":12,"is_corresponding":false},{"id":1367989,"name":"Tong Xiao","orcid":"0009-0007-7996-4134","position":13,"is_corresponding":false},{"id":890199,"name":"Anqi Li","orcid":"0000-0002-4590-8739","position":14,"is_corresponding":false},{"id":1367990,"name":"Parker Kronen","orcid":"0009-0007-6004-0740","position":15,"is_corresponding":false},{"id":14931,"name":"Nicholas Denko","orcid":"0000-0001-6875-734X","position":16,"is_corresponding":false},{"id":251305,"name":"David P. 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