{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T17:42:57Z","timestamp":1770745377931,"version":"3.49.0"},"reference-count":51,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T00:00:00Z","timestamp":1770422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016991","name":"Universidad de Guadalajara","doi-asserted-by":"crossref","award":["PRODEP-2023"],"award-info":[{"award-number":["PRODEP-2023"]}],"id":[{"id":"10.13039\/100016991","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neoadjuvant systemic therapy (NST) is standard for locally advanced breast cancer (BC), yet predictors of pathological complete response (pCR) remain elusive. While Natural Killer (NK) cells are vital for anti-tumor response, their specific receptor dynamics during NST are poorly defined. This study provides a high-dimensional characterization of the peripheral NK cell landscape and immune signatures associated with therapeutic success. This prospective cohort study included 34 BC patients and 35 healthy donors (HD). Clinical characteristics were collected, and peripheral blood NK cell subsets were evaluated. We utilized high-parameter flow cytometry and unsupervised clustering (UMAP) to longitudinally track NK cell phenotypes (NKG2D, DNAM-1, PD-1, TIGIT) pre- and post-NST. NK cell cytotoxicity was evaluated, and serum levels of related IL-17A (interleukin), IL-2, IL-4, IL-10, IL-6, TNF-\u03b1 (tumor necrosis factor-alpha), Fas, sFasL, IFN-\u03b3 (interferon-gamma), and Granzyme A were analyzed. Patients exhibited distinct NK cell profiles according to the pathological response. Only 12 BC patients achieved pCR. These patients showed improved NK cell cytotoxicity and higher concentrations of IL-2, TNF-\u03b1, sFASL, and Granzyme B after treatment compared with Non-pCR patients. In contrast, in Non-pCR patients, the percentages of CD56bright NK cells increased after neoadjuvant therapy, whereas the more cytotoxic CD56dim NK cell population decreased. Additionally, NK cells from Non-pCR patients exhibited higher co-expression of inhibitory checkpoints (TIGIT and PD-1), indicating reduced NK cell function. Otherwise, pCR patients displayed a more favorable balance of activating receptors (NKG2D and DNAM-1), and a favorable shift in the TIGIT\/DNAM-1 activating-to-inhibitory axis. This study highlights the potential role of NK cells in determining the response to neoadjuvant therapy in BC patients. Those who achieved pCR showed enhanced NK cell activity and higher expression of activating receptors. Moreover, NK cells from Non-pCR patients showed lower cytotoxicity and higher expression of inhibitory receptors. These results suggest that NK cell phenotype evaluation could serve as a biomarker of treatment response in patients with BC. They also showed that the TIGIT\/DNAM-1 axis can be a critical determinant of pCR.<\/jats:p>","DOI":"10.3390\/ijms27041634","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T08:15:54Z","timestamp":1770624954000},"page":"1634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural Killer Cell Phenotype and Function as a Predictive Factor for Treatment Response to Neoadjuvant Therapy in Breast Cancer Patients"],"prefix":"10.3390","volume":"27","author":[{"given":"Cinthya Yareli","family":"Anguiano Serrato","sequence":"first","affiliation":[{"name":"Hospital General Regional N\u00b02 El Marqu\u00e9s, Instituto Mexicano del Seguro Social, Quer\u00e9taro 76246, Quer\u00e9taro, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4675-2203","authenticated-orcid":false,"given":"Fabiola","family":"Solorzano-Ibarra","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Instituto de Investigaci\u00f3n en Enfermedades Cr\u00f3nico-Degenerativas, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Mariscal-Ramirez","sequence":"additional","affiliation":[{"name":"Unidad M\u00e9dica de Alta Especialidad, Departamento de Oncolog\u00eda M\u00e9dica, Hospital de Especialidades (UMAE, HE), Centro M\u00e9dico Nacional de Occidente Ignacio Garc\u00eda T\u00e9llez, IMSS, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Iyali","family":"Torres-Bustamante","sequence":"additional","affiliation":[{"name":"Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvia Elena","family":"Totsuka-Sutto","sequence":"additional","affiliation":[{"name":"Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge Ra\u00fal","family":"V\u00e1zquez-Urrutia","sequence":"additional","affiliation":[{"name":"Department of Medicine, The Pennsylvania State University College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aldo","family":"Alcaraz-Wong","sequence":"additional","affiliation":[{"name":"Unidad M\u00e9dica de Alta Especialidad, Departamento de Patolog\u00eda, Hospital de Especialidades (UMAE, HE), Centro M\u00e9dico Nacional de Occidente Ignacio Garc\u00eda T\u00e9llez, IMSS, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Betsab\u00e9","family":"Contreras-Haro","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n Biom\u00e9dica 02, UMAE, HE, Centro M\u00e9dico Nacional de Occidente Ignacio Garc\u00eda T\u00e9llez, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico"},{"name":"Departamento de Ciencias Biom\u00e9dicas, Centro Universitario de Tonal\u00e1 (CUT), Guadalajara 45425, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo Cesar","family":"Ortiz-Lazareno","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Inmunolog\u00eda, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,7]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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