{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T03:40:21Z","timestamp":1793072421360,"version":"4.5.0"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell'Istruzione, dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["P20223RRASS"],"award-info":[{"award-number":["P20223RRASS"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell'Istruzione, dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["P2022XZKBM"],"award-info":[{"award-number":["P2022XZKBM"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell'Istruzione, dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["P2022LZXNW"],"award-info":[{"award-number":["P2022LZXNW"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004271","name":"Sapienza Universit\u00e0 di Roma","doi-asserted-by":"publisher","award":["RM12218166C5057A"],"award-info":[{"award-number":["RM12218166C5057A"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>NK cell-based immunotherapy of solid tumors has been shown to be increasingly successful, but much effort is still needed to optimize its efficacy. This study explores the effects of treatment with low, non-toxic doses of IFN-\u03b3 and TNF-\u03b1 on the susceptibility of breast cancer (BC) cell lines (MCF-7, MDA-MB-231, and MDA-MB-468) cultured in 2D and 3D as spheroids, to NK cell-mediated antitumor function. We evaluated the expression of (i) ligands for NK cell-activating receptors on BC cells, (ii) death and adhesion molecules on BC cells, and (iii) the expression of NK cell-receptors on NK cells infiltrating BC spheroids. Cytokine treatment significantly increased the expression of FAS, TRAIL-R2, and ICAM-1 in all BC cell lines, enhancing NK cell-mediated apoptosis and promoting NK cell-tumor cell conjugate formation. Differently, the expression of ligands for activating receptors remained essentially unchanged. In BC spheroids, the treatment with IFN-\u03b3 and TNF-\u03b1 enhanced NK-cell infiltration, with increased expression of activating receptors (NKG2D, DNAM-1, NKp30, and NKp46) on infiltrating NK cells. However, regardless of treatment, markers of NK cell exhaustion, such as PD-1 and CTLA-4, were also upregulated, the latter especially in triple-negative BC (TNBC) MDA-MB-231 spheroids, thus suggesting an exhausted phenotype of NK cells infiltrating spheroids despite activation. Cytokine treatment resulted in a significant NK cell-mediated reduction in spheroid size, accompanied by an increased apoptotic state, with effects more pronounced in MCF-7 than in MDA-MB-231 spheroids. These results indicate that, although the treatment with IFN-\u03b3 and TNF-\u03b1 improves NK cell-mediated tumor interaction and apoptosis, its therapeutic efficacy may be dependent on the BC subtype, with TNBC spheroids showing greater resistance. These findings highlight the importance of the tumor microenvironment (TME) in shaping NK cell responses and suggest that combining IFN-\u03b3 and TNF-\u03b1 treatments with NK-cell-based immunotherapeutic strategies may improve treatment outcomes, particularly for more aggressive BC subtypes.<\/jats:p>","DOI":"10.1038\/s41419-025-08021-0","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T13:42:03Z","timestamp":1760622123000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Combined IFN-\u03b3 and TNF-\u03b1 treatment enhances the susceptibility of breast cancer cells and spheroids to Natural Killer cell-mediated killing"],"prefix":"10.1038","volume":"16","author":[{"given":"Francesca","family":"Barberini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Pietroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Ielpo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Lucarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Nardozi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ombretta","family":"Melaiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Benvenuto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7334-3966","authenticated-orcid":false,"given":"Chiara","family":"Focaccetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Palumbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4313-8347","authenticated-orcid":false,"given":"Federica","family":"Rossin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doriana","family":"Fruci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Olive","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Masuelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Bei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5014-430X","authenticated-orcid":false,"given":"Loredana","family":"Cifaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"8021_CR1","doi-asserted-by":"crossref","unstructured":"Lukasiewicz S, Czeczelewski M, Forma A, Baj J, Sitarz R, Stanislawek A. Breast Cancer-Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies-An Updated Review. Cancers (Basel) 2021, 13.","DOI":"10.3390\/cancers13174287"},{"key":"8021_CR2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1405491","volume":"14","author":"N Xiong","year":"2024","unstructured":"Xiong N, Wu H, Yu Z. Advancements and challenges in triple-negative breast cancer: a comprehensive review of therapeutic and diagnostic strategies. Front Oncol. 2024;14:1405491.","journal-title":"Front Oncol"},{"key":"8021_CR3","doi-asserted-by":"crossref","unstructured":"Kinnel B, Singh SK, Oprea-Ilies G, Singh R. Targeted Therapy and Mechanisms of Drug Resistance in Breast Cancer. Cancers (Basel) 2023, 15.","DOI":"10.3390\/cancers15041320"},{"key":"8021_CR4","first-page":"721","volume":"15","author":"J Wang","year":"2023","unstructured":"Wang J, Wu SG. Breast Cancer: An Overview of Current Therapeutic Strategies, Challenge, and Perspectives. Breast Cancer (Dove Med Press). 2023;15:721\u201330.","journal-title":"Breast Cancer (Dove Med Press)"},{"key":"8021_CR5","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1111\/imcb.12658","volume":"101","author":"SZF Kiaei","year":"2023","unstructured":"Kiaei SZF, Nouralishahi A, Ghasemirad M, Barkhordar M, Ghaffari S, Kheradjoo H, et al. Advances in natural killer cell therapies for breast cancer. Immunol Cell Biol. 2023;101:705\u201326.","journal-title":"Immunol Cell Biol"},{"key":"8021_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-06976-0","volume":"15","author":"L Coenon","year":"2024","unstructured":"Coenon L, Geindreau M, Ghiringhelli F, Villalba M, Bruchard M. Natural Killer cells at the frontline in the fight against cancer. Cell Death Dis. 2024;15:614.","journal-title":"Cell Death Dis"},{"key":"8021_CR7","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1038\/s41392-024-02005-w","volume":"9","author":"S Chen","year":"2024","unstructured":"Chen S, Zhu H, Jounaidi Y. Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization. Signal Transduct Target Ther. 2024;9:302.","journal-title":"Signal Transduct Target Ther"},{"key":"8021_CR8","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/cdd.2013.26","volume":"21","author":"CJ Chan","year":"2014","unstructured":"Chan CJ, Smyth MJ, Martinet L. Molecular mechanisms of natural killer cell activation in response to cellular stress. Cell Death Differ. 2014;21:5\u201314.","journal-title":"Cell Death Differ"},{"key":"8021_CR9","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.3389\/fimmu.2017.01194","volume":"8","author":"A Zingoni","year":"2017","unstructured":"Zingoni A, Fionda C, Borrelli C, Cippitelli M, Santoni A, Soriani A. Natural Killer Cell Response to Chemotherapy-Stressed Cancer Cells: Role in Tumor Immunosurveillance. Front Immunol. 2017;8:1194.","journal-title":"Front Immunol"},{"key":"8021_CR10","doi-asserted-by":"publisher","first-page":"1566","DOI":"10.1002\/eji.202049028","volume":"51","author":"L Quatrini","year":"2021","unstructured":"Quatrini L, Della Chiesa M, Sivori S, Mingari MC, Pende D, Moretta L. Human NK cells, their receptors and function. Eur J Immunol. 2021;51:1566\u201379.","journal-title":"Eur J Immunol"},{"key":"8021_CR11","doi-asserted-by":"publisher","first-page":"3038","DOI":"10.3389\/fimmu.2019.03038","volume":"10","author":"O Melaiu","year":"2019","unstructured":"Melaiu O, Lucarini V, Cifaldi L, Fruci D. Influence of the tumor microenvironment on NK cell function in solid tumors. Front Immunol. 2019;10:3038.","journal-title":"Front Immunol"},{"key":"8021_CR12","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12441","volume":"51","author":"J Shen","year":"2018","unstructured":"Shen J, Xiao Z, Zhao Q, Li M, Wu X, Zhang L, et al. Anti-cancer therapy with TNFalpha and IFNgamma: A comprehensive review. Cell Prolif. 2018;51:e12441.","journal-title":"Cell Prolif"},{"key":"8021_CR13","doi-asserted-by":"publisher","first-page":"601","DOI":"10.3389\/fimmu.2015.00601","volume":"6","author":"C Chester","year":"2015","unstructured":"Chester C, Fritsch K, Kohrt HE. Natural killer cell immunomodulation: targeting activating, inhibitory, and co-stimulatory receptor signaling for cancer immunotherapy. Front Immunol. 2015;6:601.","journal-title":"Front Immunol"},{"key":"8021_CR14","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1189\/jlb.0611308","volume":"91","author":"R Wang","year":"2012","unstructured":"Wang R, Jaw JJ, Stutzman NC, Zou Z, Sun PD. Natural killer cell-produced IFN-gamma and TNF-alpha induce target cell cytolysis through up-regulation of ICAM-1. J Leukoc Biol. 2012;91:299\u2013309.","journal-title":"J Leukoc Biol"},{"key":"8021_CR15","doi-asserted-by":"crossref","unstructured":"Brandetti E, Focaccetti C, Pezzolo A, Ognibene M, Folgiero V, Cotugno N, et al. Enhancement of neuroblastoma NK-cell-mediated lysis through NF-kB p65 subunit-induced expression of FAS and PVR, the loss of which is associated with poor patient outcome. Cancers (Basel) 2021, 13.","DOI":"10.3390\/cancers13174368"},{"key":"8021_CR16","first-page":"2832","volume":"58","author":"X Xu","year":"1998","unstructured":"Xu X, Fu XY, Plate J, Chong AS. IFN-gamma induces cell growth inhibition by Fas-mediated apoptosis: requirement of STAT1 protein for up-regulation of Fas and FasL expression. Cancer Res. 1998;58:2832\u20137.","journal-title":"Cancer Res"},{"key":"8021_CR17","doi-asserted-by":"publisher","first-page":"4398","DOI":"10.1002\/(SICI)1521-4141(199812)28:12<4398::AID-IMMU4398>3.0.CO;2-Y","volume":"28","author":"KS Spanaus","year":"1998","unstructured":"Spanaus KS, Schlapbach R, Fontana A. TNF-alpha and IFN-gamma render microglia sensitive to Fas ligand-induced apoptosis by induction of Fas expression and down-regulation of Bcl-2 and Bcl-xL. Eur J Immunol. 1998;28:4398\u2013408.","journal-title":"Eur J Immunol"},{"key":"8021_CR18","doi-asserted-by":"publisher","first-page":"743","DOI":"10.4049\/jimmunol.165.2.743","volume":"165","author":"A Riccioli","year":"2000","unstructured":"Riccioli A, Starace D, D\u2019Alessio A, Starace G, Padula F, De Cesaris P, et al. TNF-alpha and IFN-gamma regulate expression and function of the Fas system in the seminiferous epithelium. J Immunol. 2000;165:743\u20139.","journal-title":"J Immunol"},{"key":"8021_CR19","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/jid.2012.330","volume":"133","author":"I Viard-Leveugle","year":"2013","unstructured":"Viard-Leveugle I, Gaide O, Jankovic D, Feldmeyer L, Kerl K, Pickard C, et al. TNF-alpha and IFN-gamma are potential inducers of Fas-mediated keratinocyte apoptosis through activation of inducible nitric oxide synthase in toxic epidermal necrolysis. J Invest Dermatol. 2013;133:489\u201398.","journal-title":"J Invest Dermatol"},{"key":"8021_CR20","first-page":"311","volume":"18","author":"R Matsumura","year":"2000","unstructured":"Matsumura R, Umemiya K, Goto T, Nakazawa T, Ochiai K, Kagami M, et al. Interferon gamma and tumor necrosis factor alpha induce Fas expression and anti-Fas mediated apoptosis in a salivary ductal cell line. Clin Exp Rheumatol. 2000;18:311\u20138.","journal-title":"Clin Exp Rheumatol"},{"key":"8021_CR21","doi-asserted-by":"publisher","first-page":"4126","DOI":"10.1242\/jcs.009761","volume":"120","author":"H Fluhr","year":"2007","unstructured":"Fluhr H, Krenzer S, Stein GM, Stork B, Deperschmidt M, Wallwiener D, et al. Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis. J Cell Sci. 2007;120:4126\u201333.","journal-title":"J Cell Sci"},{"key":"8021_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/emm.1998.1","volume":"30","author":"A Raval","year":"1998","unstructured":"Raval A, Puri N, Rath PC, Saxena RK. Cytokine regulation of expression of class I MHC antigens. Exp Mol Med. 1998;30:1\u201313.","journal-title":"Exp Mol Med"},{"key":"8021_CR23","doi-asserted-by":"publisher","first-page":"5386","DOI":"10.1093\/emboj\/16.17.5386","volume":"16","author":"H Walczak","year":"1997","unstructured":"Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, et al. TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J. 1997;16:5386\u201397.","journal-title":"EMBO J"},{"key":"8021_CR24","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1016\/0092-8674(93)90326-L","volume":"75","author":"T Suda","year":"1993","unstructured":"Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993;75:1169\u201378.","journal-title":"Cell"},{"key":"8021_CR25","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1016\/0092-8674(87)90104-8","volume":"51","author":"SD Marlin","year":"1987","unstructured":"Marlin SD, Springer TA. Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell. 1987;51:813\u20139.","journal-title":"Cell"},{"key":"8021_CR26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1162905","volume":"14","author":"RM Visalakshan","year":"2023","unstructured":"Visalakshan RM, Lowrey MK, Sousa MGC, Helms HR, Samiea A, Schutt CE, et al. Opportunities and challenges to engineer 3D models of tumor-adaptive immune interactions. Front Immunol. 2023;14:1162905.","journal-title":"Front Immunol"},{"key":"8021_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-44789-z","volume":"15","author":"I Dean","year":"2024","unstructured":"Dean I, Lee CYC, Tuong ZK, Li Z, Tibbitt CA, Willis C, et al. Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity. Nat Commun. 2024;15:683.","journal-title":"Nat Commun"},{"key":"8021_CR28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1303605","volume":"14","author":"H Jia","year":"2023","unstructured":"Jia H, Yang H, Xiong H, Luo KQ. NK cell exhaustion in the tumor microenvironment. Front Immunol. 2023;14:1303605.","journal-title":"Front Immunol"},{"key":"8021_CR29","doi-asserted-by":"publisher","first-page":"4572","DOI":"10.4049\/jimmunol.0803900","volume":"182","author":"NT Joncker","year":"2009","unstructured":"Joncker NT, Fernandez NC, Treiner E, Vivier E, Raulet DH. NK cell responsiveness is tuned commensurate with the number of inhibitory receptors for self-MHC class I: the rheostat model. J Immunol. 2009;182:4572\u201380.","journal-title":"J Immunol"},{"key":"8021_CR30","doi-asserted-by":"publisher","first-page":"2434","DOI":"10.1182\/blood-2008-05-156836","volume":"113","author":"P Brodin","year":"2009","unstructured":"Brodin P, Lakshmikanth T, Johansson S, Karre K, Hoglund P. The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells. Blood. 2009;113:2434\u201341.","journal-title":"Blood"},{"key":"8021_CR31","doi-asserted-by":"publisher","first-page":"35","DOI":"10.3233\/BD-2010-0307","volume":"32","author":"KJ Chavez","year":"2010","unstructured":"Chavez KJ, Garimella SV, Lipkowitz S. Triple negative breast cancer cell lines: one tool in the search for better treatment of triple negative breast cancer. Breast Dis. 2010;32:35\u201348.","journal-title":"Breast Dis"},{"key":"8021_CR32","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.3389\/fimmu.2017.01124","volume":"8","author":"S Paul","year":"2017","unstructured":"Paul S, Lal G. The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy. Front Immunol. 2017;8:1124.","journal-title":"Front Immunol"},{"key":"8021_CR33","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/s41586-023-06816-9","volume":"625","author":"A Cui","year":"2024","unstructured":"Cui A, Huang T, Li S, Ma A, Perez JL, Sander C, et al. Dictionary of immune responses to cytokines at single-cell resolution. Nature. 2024;625:377\u201384.","journal-title":"Nature"},{"key":"8021_CR34","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1177\/1091581815584918","volume":"34","author":"T Ramani","year":"2015","unstructured":"Ramani T, Auletta CS, Weinstock D, Mounho-Zamora B, Ryan PC, Salcedo TW, et al. Cytokines: The Good, the Bad, and the Deadly. Int J Toxicol. 2015;34:355\u201365.","journal-title":"Int J Toxicol"},{"key":"8021_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1749-6632.2009.05382.x","volume":"1182","author":"RP Donnelly","year":"2009","unstructured":"Donnelly RP, Young HA, Rosenberg AS. An overview of cytokines and cytokine antagonists as therapeutic agents. Ann N. Y Acad Sci. 2009;1182:1\u201313.","journal-title":"Ann N. Y Acad Sci"},{"key":"8021_CR36","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2021.113896","volume":"176","author":"A Nash","year":"2021","unstructured":"Nash A, Aghlara-Fotovat S, Hernandez A, Scull C, Veiseh O. Clinical translation of immunomodulatory therapeutics. Adv Drug Deliv Rev. 2021;176:113896.","journal-title":"Adv Drug Deliv Rev"},{"key":"8021_CR37","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1007\/s40264-014-0226-z","volume":"37","author":"BA Baldo","year":"2014","unstructured":"Baldo BA. Side effects of cytokines approved for therapy. Drug Saf. 2014;37:921\u201343.","journal-title":"Drug Saf"},{"key":"8021_CR38","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1111\/j.1365-2613.2001.iep192.x","volume":"82","author":"JR Foster","year":"2001","unstructured":"Foster JR. The functions of cytokines and their uses in toxicology. Int J Exp Pathol. 2001;82:171\u201392.","journal-title":"Int J Exp Pathol"},{"key":"8021_CR39","first-page":"84","volume":"9","author":"DJ Propper","year":"2003","unstructured":"Propper DJ, Chao D, Braybrooke JP, Bahl P, Thavasu P, Balkwill F, et al. Low-dose IFN-gamma induces tumor MHC expression in metastatic malignant melanoma. Clin Cancer Res. 2003;9:84\u201392.","journal-title":"Clin Cancer Res"},{"key":"8021_CR40","doi-asserted-by":"publisher","first-page":"739","DOI":"10.18632\/oncotarget.344","volume":"2","author":"NJ Roberts","year":"2011","unstructured":"Roberts NJ, Zhou S, Diaz LA Jr, Holdhoff M. Systemic use of tumor necrosis factor alpha as an anticancer agent. Oncotarget. 2011;2:739\u201351.","journal-title":"Oncotarget"},{"key":"8021_CR41","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1002\/1097-0215(20000915)87:6<829::AID-IJC12>3.0.CO;2-C","volume":"87","author":"TL Ten Hagen","year":"2000","unstructured":"Ten Hagen TL, Van Der Veen AH, Nooijen PT, Van Tiel ST, Seynhaeve AL, Eggermont AM. Low-dose tumor necrosis factor-alpha augments antitumor activity of stealth liposomal doxorubicin (DOXIL) in soft tissue sarcoma-bearing rats. Int J Cancer. 2000;87:829\u201337.","journal-title":"Int J Cancer"},{"key":"8021_CR42","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-018-1611-7","volume":"16","author":"SF Josephs","year":"2018","unstructured":"Josephs SF, Ichim TE, Prince SM, Kesari S, Marincola FM, Escobedo AR, et al. Unleashing endogenous TNF-alpha as a cancer immunotherapeutic. J Transl Med. 2018;16:242.","journal-title":"J Transl Med"},{"key":"8021_CR43","doi-asserted-by":"crossref","unstructured":"Sordo-Bahamonde C, Lorenzo-Herrero S, Payer AR, Gonzalez S, Lopez-Soto A Mechanisms of Apoptosis Resistance to NK Cell-Mediated Cytotoxicity in Cancer. Int J Mol Sci. 2020, 21.","DOI":"10.3390\/ijms21103726"},{"key":"8021_CR44","doi-asserted-by":"publisher","first-page":"5530","DOI":"10.1111\/febs.15637","volume":"288","author":"L Cardoso Alves","year":"2021","unstructured":"Cardoso Alves L, Corazza N, Micheau O, Krebs P. The multifaceted role of TRAIL signaling in cancer and immunity. FEBS J. 2021;288:5530\u201354.","journal-title":"FEBS J"},{"key":"8021_CR45","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1084\/jem.188.12.2375","volume":"188","author":"L Zamai","year":"1998","unstructured":"Zamai L, Ahmad M, Bennett IM, Azzoni L, Alnemri ES, Perussia B. Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells. J Exp Med. 1998;188:2375\u201380.","journal-title":"J Exp Med"},{"key":"8021_CR46","doi-asserted-by":"publisher","first-page":"391","DOI":"10.3389\/fimmu.2017.00391","volume":"8","author":"A Aquino-Lopez","year":"2017","unstructured":"Aquino-Lopez A, Senyukov VV, Vlasic Z, Kleinerman ES, Lee DA. Interferon Gamma Induces Changes in Natural Killer (NK) Cell Ligand Expression and Alters NK Cell-Mediated Lysis of Pediatric Cancer Cell Lines. Front Immunol. 2017;8:391.","journal-title":"Front Immunol"},{"key":"8021_CR47","doi-asserted-by":"crossref","unstructured":"Eitler J, Rackwitz W, Wotschel N, Gudipati V, Murali Shankar N, Sidorenkova A, et al. CAR-mediated targeting of NK cells overcomes tumor immune escape caused by ICAM-1 downregulation. J Immunother Cancer 2024, 12.","DOI":"10.1136\/jitc-2023-008155"},{"key":"8021_CR48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1176647","volume":"14","author":"Q Zhou","year":"2023","unstructured":"Zhou Q, Xu J, Xu Y, Sun S, Chen J. Role of ICAM1 in tumor immunity and prognosis of triple-negative breast cancer. Front Immunol. 2023;14:1176647.","journal-title":"Front Immunol"},{"key":"8021_CR49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1135148","volume":"14","author":"V Carannante","year":"2023","unstructured":"Carannante V, Wiklund M, Onfelt B. In vitro models to study natural killer cell dynamics in the tumor microenvironment. Front Immunol. 2023;14:1135148.","journal-title":"Front Immunol"},{"key":"8021_CR50","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-015-1321-y","volume":"15","author":"A Giannattasio","year":"2015","unstructured":"Giannattasio A, Weil S, Kloess S, Ansari N, Stelzer EH, Cerwenka A, et al. Cytotoxicity and infiltration of human NK cells in in vivo-like tumor spheroids. BMC Cancer. 2015;15:351.","journal-title":"BMC Cancer"},{"key":"8021_CR51","doi-asserted-by":"publisher","first-page":"760","DOI":"10.3389\/fimmu.2017.00760","volume":"8","author":"J Bi","year":"2017","unstructured":"Bi J, Tian Z. NK Cell Exhaustion. Front Immunol. 2017;8:760.","journal-title":"Front Immunol"},{"key":"8021_CR52","doi-asserted-by":"crossref","unstructured":"Nedeljkovic M, Damjanovic A. Mechanisms of chemotherapy resistance in triple-negative breast cancer-how we can rise to the challenge. Cells 2019, 8.","DOI":"10.3390\/cells8090957"},{"key":"8021_CR53","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1153990","volume":"14","author":"Y Zheng","year":"2023","unstructured":"Zheng Y, Li S, Tang H, Meng X, Zheng Q. Molecular mechanisms of immunotherapy resistance in triple-negative breast cancer. Front Immunol. 2023;14:1153990.","journal-title":"Front Immunol"}],"updated-by":[{"DOI":"10.1038\/s41419-025-08381-7","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000}}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08021-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08021-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08021-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T08:03:48Z","timestamp":1769069028000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08021-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,16]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["8021"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-08021-0","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,16]]},"assertion":[{"value":"21 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 July 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 September 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 October 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 December 2025","order":6,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":7,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The original online version of this article was revised: In the \u201cMaterials and Methods\u201d section and \u201cBC cell lines, spheroid formation and cytokine treatment\u201d subsection two sentences have been updated. In the text, there is a typographical error regarding the concentration of IFN-\u03b3 and TNF-\u03b1 cytokines used in the experiments, which is incorrectly reported in micrograms (\u03bcg) instead of nanograms (ng).","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2026","order":9,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":10,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":11,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41419-025-08381-7","URL":"https:\/\/doi.org\/10.1038\/s41419-025-08381-7","order":12,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"D.O. is a cofounder and shareholder of ImCheck Therapeutics, Alderaan Biotechnology and Emergence Therapeutics and has research funds from ImCheck Therapeutics, Alderaan Biotechnology, Cellectis and Emergence Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. No samples from patients were used in this study. NK cells were isolated from buffy-coats obtained from healthy donors, according to the standard procedure of our institutional blood transfusion center (Bambino Ges\u00f9 Children\u2019s Hospital, Rome, Italy), who signed a written informed consent, in accordance with rules set by the Institutional Review Board of OPBG (Approval of Ethical Committee No. 1267\/2016 prot. No. 348).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"729"}}