{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T15:09:19Z","timestamp":1788793759045,"version":"build-2803163510"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"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. Chem."],"abstract":"<jats:p>Copper is an essential micronutrient whose redox activity underpins a dual role in immunity: it serves as both an antimicrobial effector and a regulator of inflammatory signaling. Macrophages, as central orchestrators of innate and adaptive immunity, maintain sophisticated copper homeostasis mechanisms that dynamically adapt to distinct activation states and environmental cues. This review synthesizes current knowledge around three interconnected themes: (1) the molecular machinery governing copper transport and regulation\u2014including CTR1, ATP7A, ATP7B, and copper chaperones; (2) the functional interplay between copper metabolism, macrophage polarization, and immunometabolism; and (3) the pathophysiological consequences of copper dysregulation in infection, chronic inflammation, and cancer. Emerging evidence reveals that copper exerts dose-dependent effects on macrophage polarization: low-to-moderate copper promotes an anti-inflammatory M2 phenotype via STAT6 and PI3K\/Akt pathways, whereas high copper concentrations trigger oxidative stress and NF-\u03baB activation, driving pro-inflammatory M1 polarization. Furthermore, recent findings highlight crosstalk among copper metabolism, cuproptosis, and tumor-associated macrophage function, opening new avenues for copper-based immunotherapy. This review identifies critical knowledge gaps\u2014including tissue-specific copper regulation, single-cell dynamics of copper trafficking, and the therapeutic potential of copper-targeted interventions. While acknowledging the bidirectional causality between copper metabolism and macrophage activation, we argue that copper homeostasis functions as a rheostat of immune competence with substantial translational promise.<\/jats:p>","DOI":"10.3389\/fchem.2026.1924097","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T14:25:17Z","timestamp":1788791117000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Copper homeostasis in macrophages: regulatory mechanisms and immunological implications"],"prefix":"10.3389","volume":"14","author":[{"given":"Wanting","family":"Yang","sequence":"first","affiliation":[{"name":"The State Key Laboratory of Organic-Inorganic Composites, The Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Organic-Inorganic Composites, The Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenbin","family":"Dong","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Organic-Inorganic Composites, The Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangming","family":"Zhang","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Organic-Inorganic Composites, The Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guofeng","family":"Li","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Organic-Inorganic Composites, The Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Wang","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Organic-Inorganic Composites, The Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wensheng","family":"Xie","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Organic-Inorganic Composites, The Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1016\/j.tim.2021.01.004","article-title":"Copper handling in the salmonella cell envelope and its impact on virulence","volume":"29","author":"Checa","year":"2021","journal-title":"Trends Microbiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/s41392-022-01229-y","article-title":"Copper homeostasis and cuproptosis in health and disease","volume":"7","author":"Chen","year":"2022","journal-title":"Signal Transduct. 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