{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T01:18:34Z","timestamp":1777943914392,"version":"3.51.4"},"reference-count":150,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T00:00:00Z","timestamp":1771027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Breast cancer (BC) is a global health problem. BC is a biologically heterogeneous disease in which novel immunotherapeutic strategies are needed, particularly in the metastatic setting. The NKG2D\/NKG2D ligand (NKG2DL) axis is a key component of innate antitumor immunity and represents a potential therapeutic target, but its relevance in BC has not been fully characterized. We performed an in silico analysis of NKG2DL expression in BC cell lines, healthy breast tissue, and tumor samples using publicly available transcriptomic databases (DSMZCellDive, ShinyTHOR, GTEx, TCGA, Human Protein Atlas), complemented by survival analyses from TCGA and KMPlot and a narrative review of the literature. NKG2DL transcripts were consistently expressed in BC cell lines and tumor tissues, with higher expression observed in ductal histology, higher tumor stage, and basal molecular subtype. Survival analyses showed heterogeneous and generally weak associations between individual NKG2DLs and clinical outcomes. In silico proteomics data are scarce, but the narrative review showed that NKG2DLs are expressed by immunohistochemistry in tumor tissues but absent in surrounding healthy tissues. The literature review also revealed concomitant dysfunction of NKG2D+ effector cells due to multiple resistance mechanisms (including ligand shedding). We also review potential therapeutic approaches.<\/jats:p>","DOI":"10.3390\/ijms27041848","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T10:14:32Z","timestamp":1771236872000},"page":"1848","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NKGD2 Ligands (NKG2DLs) in Breast Cancer: In Silico Analysis and Narrative Review"],"prefix":"10.3390","volume":"27","author":[{"given":"Jes\u00fas","family":"Pe\u00f1a-L\u00f3pez","sequence":"first","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario La Paz, Universidad Aut\u00f3noma, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8931-0624","authenticated-orcid":false,"given":"Angelo","family":"G\u00e1mez-Pozo","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, IdiPAZ-Instituto de Investigacion Sanitaria del Hospital Universitario La Paz, 28029 Madrid, Spain"},{"name":"CIBERONC-ISCIII (Biomedical Research Networking Center on Oncology\u2014Carlos III Health Institute), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4452-3474","authenticated-orcid":false,"given":"Luc\u00eda","family":"Trilla-Fuertes","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, IdiPAZ-Instituto de Investigacion Sanitaria del Hospital Universitario La Paz, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3726-050X","authenticated-orcid":false,"given":"Fernando","family":"Becerril-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, IdiPAZ-Instituto de Investigacion Sanitaria del Hospital Universitario La Paz, 28029 Madrid, Spain"},{"name":"CIBERONC-ISCIII (Biomedical Research Networking Center on Oncology\u2014Carlos III Health Institute), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Mendiola","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, IdiPAZ-Instituto de Investigacion Sanitaria del Hospital Universitario La Paz, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Heredia","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory, Institute of Medical and Molecular Genetics-INGEMM, IdiPAZ-Instituto de Investigacion Sanitaria del Hospital Universitario La Paz, 28029 Madrid, Spain"},{"name":"CIBERONC-ISCIII (Biomedical Research Networking Center on Oncology\u2014Carlos III Health Institute), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Y\u00e9benes","sequence":"additional","affiliation":[{"name":"Department of Pathology, Hospital Universitario La Paz, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5824-9808","authenticated-orcid":false,"given":"Beatriz","family":"Castelo","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario La Paz, Universidad Aut\u00f3noma, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"Mart\u00ednez-Mar\u00edn","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario La Paz, Universidad Aut\u00f3noma, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6562-7902","authenticated-orcid":false,"given":"Enrique","family":"Espinosa","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario La Paz, Universidad Aut\u00f3noma, 28046 Madrid, Spain"},{"name":"CIBERONC-ISCIII (Biomedical Research Networking Center on Oncology\u2014Carlos III Health Institute), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pilar","family":"Zamora","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Universitario La Paz, Universidad Aut\u00f3noma, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfonso","family":"Alba-Bernal","sequence":"additional","affiliation":[{"name":"CIBERER-ISCIII (Biomedical Research Networking Center on Rare Diseases\u2014Carlos III Health Institute), IdiPAZ-CNIO Pediatric Onco-Hematology Clinical Research Unit, IdiPAZ-Instituto de Investigacion Sanitaria del Hospital Universitario La Paz, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Aguirre-Portol\u00e9s","sequence":"additional","affiliation":[{"name":"CIBERER-ISCIII (Biomedical Research Networking Center on Rare Diseases\u2014Carlos III Health Institute), IdiPAZ-CNIO Pediatric Onco-Hematology Clinical Research Unit, IdiPAZ-Instituto de Investigacion Sanitaria del Hospital Universitario La Paz, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6436-9195","authenticated-orcid":false,"given":"Antonio","family":"P\u00e9rez-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"CIBERER-ISCIII (Biomedical Research Networking Center on Rare Diseases\u2014Carlos III Health Institute), IdiPAZ-CNIO Pediatric Onco-Hematology Clinical Research Unit, IdiPAZ-Instituto de Investigacion Sanitaria del Hospital Universitario La Paz, 28029 Madrid, Spain"},{"name":"Pediatric Hemato-Oncology Department, Hospital Universitario La Paz, Universidad Aut\u00f3noma, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,14]]},"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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