{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T23:02:14Z","timestamp":1784847734764,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,21]]},"group-title":"Immunology","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["P20GM135004"],"award-info":[{"award-number":["P20GM135004"]}]},{"name":"NIH","award":["R01CA278941"],"award-info":[{"award-number":["R01CA278941"]}]},{"name":"NIH","award":["1R21CA288604-01A1"],"award-info":[{"award-number":["1R21CA288604-01A1"]}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"crossref","award":["MBGI-23-1150374-01-MBG"],"award-info":[{"award-number":["MBGI-23-1150374-01-MBG"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,21]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Macrophages in breast cancer are highly heterogeneous and targeting both tissue-resident and bone marrow-derived macrophages represents a high-potential strategy in breast cancer immunotherapy.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Myeloid-specific Egr2 knockout (KO) mice were used to determine roles of macrophage Egr2 signaling in tumor progression and anti-tumor immune responses. RNA-seq analysis and Flow cytometry were used to examine regulation of Egr2 in tumor-associated macrophages (TAMs) and fatty acid-stimulated macrophages. Tumor cell and macrophage admixture study was used to evaluate effects of fatty acid educated macrophages on anti-tumor responses.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Here we showed that early growth response 2 (Egr2) was highly expressed in mammary tissue macrophages and recruited macrophages upon tumor progression. Depletion of Egr2 in myeloid cells significantly decreased the immunosuppressive function of polarized M2-like macrophages and TAMs. Tumor progression was delayed in myeloid cell Egr2 knockout mice, which was associated with enhanced function of effector CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells and NK cells. Mechanistically, we showed that retinol and nicotinamide metabolism in TAMs were impaired after Egr2 depletion. Further, tumor cell-derived stearic acid (SA) was identified as an important fatty acid inducing Egr2 expression. SA stimulation induced macrophage-mediated immunosuppression in an Egr2 dependent manner. Addition of oleic acid (OA) uniquely repressed SA-induced Egr2 expression and immunosuppressive activity in macrophages.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our study thus uncovers a novel SA-Egr2 pathway driving macrophage immunosuppression and novel molecular mechanism of OA mediated anti-tumor effect.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>WHAT IS ALREADY KNOWN ON THIS TOPIC<\/jats:title>\n                  <jats:p>Lipid-associated macrophages (LAMs) accumulate lipids and promote immune suppression, tumor growth and metastasis in breast cancers. Fatty acids play a dual, complex role in tumor immunity, acting as both pro-tumorigenic and anti-tumorigenic effects. However, molecular mechanisms underlying fatty acid modulated macrophages and their roles in tumor remain not fully elucidated.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>WHAT THIS STUDY ADDS<\/jats:title>\n                  <jats:p>We demonstrate that Egr2 is essential for the immunosuppressive function of IL-4 polarized M2-like macrophages and TAMs. Tumor cell-derived stearic acid (SA) was identified as an important fatty acid inducing Egr2 expression and immunosuppression in macrophages. Adding oleic acid (OA) uniquely repressed SA-induced Egr2 expression and immunosuppression.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY<\/jats:title>\n                  <jats:p>SA-Egr2 axis is a novel pathway driving macrophage immunosuppression. OA treatment enhances macrophage anti-tumor immunity via inhibiting Egr2 signaling and immunosuppression. The data supports the notion that diets enriched in OA may have potential for prevention and suppression of breast cancer.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.15.738781","type":"posted-content","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T17:40:16Z","timestamp":1784655616000},"source":"Crossref","is-referenced-by-count":0,"title":["Tumor-derived stearic acid induces macrophage Egr2 signaling to suppress anti-tumor immunity in breast cancer"],"prefix":"10.64898","author":[{"given":"Yongling","family":"Ning","sequence":"first","affiliation":[{"name":"UofL Health Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caijun","family":"Wu","sequence":"additional","affiliation":[{"name":"UofL Health Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sailesh","family":"Phuyal","sequence":"additional","affiliation":[{"name":"UofL Health Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Hu","sequence":"additional","affiliation":[{"name":"UofL Health Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Li","sequence":"additional","affiliation":[{"name":"UofL Health Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"Mitchell","sequence":"additional","affiliation":[{"name":"The Hiram C. Polk, Jr., MD Department of Surgery, Division of Immunotherapy, UofL Health Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA"},{"name":"UofL Health Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yan","sequence":"additional","affiliation":[{"name":"The Hiram C. Polk, Jr., MD Department of Surgery, Division of Immunotherapy, UofL Health Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA"},{"name":"UofL Health Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9588-6403","authenticated-orcid":false,"given":"Chuanlin","family":"Ding","sequence":"additional","affiliation":[{"name":"The Hiram C. 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