{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:16:32Z","timestamp":1786115792734,"version":"build-2736575974"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Lipid metabolic reprogramming is increasingly recognized as a driver of breast cancer progression; however, how lipid metabolism-associated risk states are translated into immune remodeling and epithelial\u2013mesenchymal transition (EMT) remains unclear. This study aimed to identify a lipid metabolism-related regulator that mediates tumor\u2013macrophage crosstalk and to experimentally define its role in breast cancer progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Lipid metabolism-related immune regulatory candidates were identified through integrated bulk transcriptomic, machine-learning, single-cell, and spatial transcriptomic analyses. UNC93B1 was prioritized for experimental validation using immunohistochemistry, gain- and loss-of-function assays, tumor cell\u2013macrophage co-culture, ELISA, IL-6 neutralization, and STAT3 inhibition\/rescue experiments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Integrated multi-omics analysis prioritized UNC93B1 as a lipid metabolism-associated immune regulatory hub in breast cancer. UNC93B1 was associated with high lipid metabolism risk status, invasive tumor phenotypes, and stronger expression in aggressive molecular contexts, particularly HER2-enriched and triple-negative breast cancer samples. Single-cell and spatial transcriptomic analyses further linked UNC93B1 to myeloid\/macrophage-enriched states, M2-like macrophage polarization, and Toll-like receptor-related immune niches. Experimentally, UNC93B1 knockdown suppressed breast cancer cell proliferation, migration, invasion, STAT3 activation, and EMT, whereas UNC93B1 overexpression produced the opposite effects. In tumor cell\u2013macrophage co-culture systems, tumor cell-derived UNC93B1 enhanced IL-6 secretion, activated STAT3 signaling in macrophages, and promoted M2-like polarization. Reciprocally, macrophage-associated IL-6\/STAT3 signaling reinforced EMT and invasive behavior in breast cancer cells. IL-6 neutralization and STAT3 inhibition markedly disrupted this paracrine feedback loop, confirming that UNC93B1 promotes breast cancer progression through an IL-6\/STAT3-dependent tumor\u2013macrophage crosstalk axis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study identifies UNC93B1 as a macrophage-associated immune regulatory factor linked to lipid metabolism-related risk in breast cancer. Integrated multi-omics analyses and functional experiments demonstrate that UNC93B1 promotes IL-6\/STAT3-dependent tumor\u2013macrophage communication, thereby enhancing M2-like macrophage polarization, EMT activation, and invasive tumor behavior. These findings support UNC93B1 as a potential biomarker and intervention target in immunologically aggressive breast cancer. However, the direct role of UNC93B1 in lipid metabolic remodeling remains to be validated through lipidomic and metabolic flux analyses, and its tumor- and microenvironment-dependent effects require further confirmation in orthotopic or immune-competent\n                      <jats:italic>in vivo<\/jats:italic>\n                      breast cancer models.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1887125","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T05:32:00Z","timestamp":1785994320000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["UNC93B1 drives IL-6\/STAT3-dependent tumor\u2013macrophage crosstalk and epithelial\u2013mesenchymal transition in breast cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Xinpeng","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.ccell.2023.01.009","article-title":"Metabolic programming and immune suppression in the tumor microenvironment","volume":"41","author":"Arner","year":"2023","journal-title":"Cancer Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"614468","DOI":"10.3389\/fonc.2020.614468","article-title":"Inflammation-driven breast tumor cell plasticity: stemness\/emt, therapy resistance and dormancy","volume":"10","author":"Baram","year":"2020","journal-title":"Front. 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