{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T01:17:22Z","timestamp":1787879842932,"version":"build-2784847793"},"reference-count":59,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":125,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tumor\u2010associated macrophages (TAMs) are key regulators of immune homeostasis within the tumor microenvironment (TME) and play critical roles in malignant progression. However, the molecular mechanisms linking macrophage metabolic remodeling to immune regulation remain incompletely understood. Glycine cleavage system H protein (GCSH), a core regulator of copper\u2010dependent cell death, has been implicated in metabolic regulation in triple\u2010negative breast cancer (TNBC), suggesting a potential role in macrophage\u2010mediated TME remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated single\u2010cell RNA sequencing and spatial transcriptomic data from TNBC tissues to systematically characterize macrophage subpopulations with high GCSH expression. Pseudotime trajectory analysis, cuproptosis\u2010related scoring, cell\u2013cell communication inference, metabolic pathway enrichment, and spatial localization analyses were performed to delineate their functional heterogeneity and microenvironmental context. In addition, mutation profiling, immunogenomic analysis, drug sensitivity prediction, and in vitro and in vivo functional experiments were conducted to comprehensively evaluate the biological and therapeutic relevance of GCSH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>GCSH expression was predominantly enriched in macrophages, particularly in early activated subsets, and was associated with enhanced amino acid and lipid metabolic activity. GCSH\u2009+\u2009macrophages exhibited extensive interactions with T cells via pathways such as MIF\u2013CD74\u2013CXCR4 and LGALS9\u2013CD45, contributing to an immunosuppressive, tumor\u2010promoting microenvironment. Spatial analysis revealed their preferential localization at the tumor core\u2013stroma interface. Notably, GCSH missense mutations were associated with increased M1 macrophage infiltration and enrichment of immune and inflammatory pathways. Clinically, high GCSH expression correlated with poor survival, genomic instability, and chemotherapy resistance. Functional experiments demonstrated that GCSH silencing suppressed tumor cell proliferation, migration, and clonogenicity, induced apoptosis, enhanced proinflammatory cytokine secretion, and significantly inhibited tumor growth in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>GCSH acts as a central molecular link between macrophage metabolic reprogramming, immune suppression, and TNBC progression, highlighting its potential as both a prognostic biomarker and therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/7893655","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T06:42:47Z","timestamp":1778136167000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multiomics Characterization of GCSH\u2009+\u2009Macrophages Reveals Therapeutic Vulnerabilities and Immune\u2013Metabolic Crosstalk in Triple\u2010Negative Breast Cancer"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1740-3334","authenticated-orcid":false,"given":"Jiahao","family":"Ge","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9878-4955","authenticated-orcid":false,"given":"Ting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9585-9471","authenticated-orcid":false,"given":"Yuanyuan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0302-5699","authenticated-orcid":false,"given":"Shuzhen","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2025.114989"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.02.004"},{"key":"e_1_2_12_3_2","first-page":"4074","article-title":"Pan-Cancer Profiles of the Cuproptosis Gene Set","volume":"12","author":"Liu H.","year":"2022","journal-title":"American Journal of Cancer Research"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2025.07.007"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16030512"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-024-01589-8"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12011-024-04333-y"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.7150\/jca.92327"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13122955"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e21506"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-025-14151-7"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2010.08.013"},{"key":"e_1_2_12_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm882"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr988"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_2_12_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad821"},{"key":"e_1_2_12_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"e_1_2_12_18_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-021-04302-5"},{"key":"e_1_2_12_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.07.041"},{"key":"e_1_2_12_20_2","doi-asserted-by":"crossref","unstructured":"JiangX. 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