{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T06:53:07Z","timestamp":1767768787054,"version":"3.48.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Despite the revolutionary success of chimeric antigen receptor (CAR) therapy in hematologic malignancies, its application in solid tumors is hindered by the scarcity of tumor-specific membrane antigens rigorously validated in clinical specimens. Here, we identified glutamate metabotropic receptor 4 (GRM4) as a novel target with dual advantages: breast cancer (BC)-predominant membrane expression and restricted normal tissue distribution, potentially circumventing on-target off-tumor toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Through integrative multi-database analysis (DESeq2\/edgeR\/limma differential screening, CellMarker filtration, the Human Protein Atlas database validation), GRM4 was prioritized. Its expression was validated in non-malignant organs [immunohistochemistry (IHC)], BC cell lines [western blot (WB)\/quantitative polymerase chain reaction (qPCR)\/immunofluorescence (IF)], 158 BC clinical samples with paired para-cancerous tissues (IHC). Subcellular localization, tumor proportion score, and subtype-specific distribution were analyzed. Clinical correlations and survival outcomes were evaluated using chi-square tests and Kaplan-Meier analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Membrane expression was confirmed by IHC in 35.44% of clinical cases, and its presence in breast cancer cell lines was validated by WB, qPCR, and IF. GRM4 exhibited tumor-specific membrane\/cytoplasmic expression in 80.38% of BC patients (127\/158) across all subtypes (\u226570% positivity), with 51.27% showing &amp;gt;50% tumor cell positivity. Critically, GRM4 was absent in normal breast\/para-cancerous tissues and confined to the brain in non-malignant organs. While GRM4 correlated with advanced clinical stage (p=0.025) and age (p=0.026), it was independent of overall survival (p=0.449).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>GRM4 emerges as a novel CAR-associated target for breast cancer, demonstrating tumor-specific overexpression, brain-restricted normal expression, and pan-subtype applicability with potential on-target off-tumor effect.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2025.1654977","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T06:51:59Z","timestamp":1767768719000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Glutamate metabotropic receptor 4 in breast cancer: a potential and specific target for chimeric antigen receptor therapy"],"prefix":"10.3389","volume":"15","author":[{"given":"Yien","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayidana","family":"Hayierhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zexiao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumei","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaoliang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruyi","family":"Mei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoling","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pingnan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jundong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.35278","article-title":"The GLOBOCAN 2022 cancer estimates: Data sources, methods, and a snapshot of the Q24 cancer burden worldwide","volume":"156","author":"Filho","year":"2025","journal-title":"Int J Cancer"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2147\/BCTT.S432526","article-title":"Breast cancer: an overview of current therapeutic strategies, challenge, and perspectives","volume":"15","author":"Wang","year":"2023","journal-title":"Breast Cancer (Dove Med Press)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709919","article-title":"Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia","volume":"378","author":"Park","year":"2018","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707447","article-title":"Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma","volume":"377","author":"Neelapu","year":"2017","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1708566","article-title":"Chimeric antigen receptor T cells in refractory B-cell lymphomas","volume":"377","author":"Schuster","year":"2017","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1914347","article-title":"KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma","volume":"382","author":"Wang","year":"2020","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2030164","article-title":"Lymphoma program investigators at the university of P. 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