{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:33:57Z","timestamp":1793198037055,"version":"4.5.0"},"reference-count":92,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":69,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["F32CA239436"],"award-info":[{"award-number":["F32CA239436"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"U.S. Department of Health & Human Services | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["K99R00CA266748"],"award-info":[{"award-number":["K99R00CA266748"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Colorado Cancer League"},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-19-BCRP-EA"],"award-info":[{"award-number":["W81XWH-19-BCRP-EA"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-20-1-0617"],"award-info":[{"award-number":["W81XWH-20-1-0617"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The heme catabolism pathway is often elevated in aggressive cancers; however, the impact of this pathway and some of its byproducts on the tumor microenvironment remain largely unknown. In human breast cancers, tumor expression of the heme catabolizing enzyme heme oxygenase-1 (HO-1\/\n                    <jats:italic>HMOX1<\/jats:italic>\n                    ) is positively associated with macrophage abundance. In mouse mammary tumors, knockdown of\n                    <jats:italic>Hmox1<\/jats:italic>\n                    significantly decreased tumor growth and lung metastasis. Analysis of mammary tumor interstitial fluid compared to matching plasma revealed that the heme metabolite bilirubin was elevated intratumorally, which could be partially reversed via\n                    <jats:italic>Hmox1<\/jats:italic>\n                    knockdown. Further investigation revealed that bilirubin nearly ablates macrophage engulfment of dead tumor cells and significantly increases macrophage T cell suppression. Mammary tumors harboring\n                    <jats:italic>Hmox1<\/jats:italic>\n                    knockdown had a significant decrease in tumor growth rate and number of pro-metastatic CD206\n                    <jats:sup>+<\/jats:sup>\n                    macrophages upon treatment with \u03b1PD-1. Depletion of intratumoral bilirubin levels impacts pro-tumor macrophage populations, particularly in combination with immunotherapy, demonstrating that heme catabolism and bilirubin act as immunomodulators in cancer.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-10212-0","type":"journal-article","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T12:17:43Z","timestamp":1778329063000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aggressive breast cancers secrete heme metabolites to alter macrophage immune suppression and function"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7063-9147","authenticated-orcid":false,"given":"Michelle M.","family":"Williams","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6311-8191","authenticated-orcid":false,"given":"Jessica L.","family":"Christenson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole S.","family":"Spoelstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina A.","family":"Hafeez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Wei","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyndsey S.","family":"Crump","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen I.","family":"O\u2019Neill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3544-6686","authenticated-orcid":false,"given":"Alexis A.","family":"Hill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2210-7191","authenticated-orcid":false,"given":"Angelica","family":"Phan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M.","family":"McCue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Hintelmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanantonio","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley E.","family":"Sax","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2082-8553","authenticated-orcid":false,"given":"Jared","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meher Preethi","family":"Boorgula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Goodspeed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3820-1724","authenticated-orcid":false,"given":"Jill E.","family":"Slansky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9960-0991","authenticated-orcid":false,"given":"Jennifer K.","family":"Richer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"10212_CR1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/S1470-2045(19)30689-8","volume":"21","author":"P Schmid","year":"2020","unstructured":"Schmid, P. et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 21, 44\u201359 (2020).","journal-title":"Lancet Oncol."},{"key":"10212_CR2","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1158\/1541-7786.MCR-18-0246","volume":"17","author":"TJ Rogers","year":"2019","unstructured":"Rogers, T. J. et al. Reversal of Triple-Negative Breast Cancer EMT by miR-200c Decreases Tryptophan Catabolism and a Program of Immunosuppression. Mol. Cancer Res. 17, 30\u201341 (2019).","journal-title":"Mol. Cancer Res."},{"key":"10212_CR3","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-021-00273-1","volume":"7","author":"MM Williams","year":"2021","unstructured":"Williams, M. M. et al. MicroRNA-200c restoration reveals a cytokine profile to enhance M1 macrophage polarization in breast cancer. NPJ Breast Cancer 7, 64 (2021).","journal-title":"NPJ Breast Cancer"},{"key":"10212_CR4","doi-asserted-by":"publisher","first-page":"3982","DOI":"10.1158\/0008-5472.CAN-16-3292","volume":"77","author":"A Dongre","year":"2017","unstructured":"Dongre, A. et al. Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res. 77, 3982\u20133989 (2017).","journal-title":"Cancer Res."},{"key":"10212_CR5","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1158\/2159-8290.CD-20-0603","volume":"11","author":"A Dongre","year":"2021","unstructured":"Dongre, A. et al. Direct and indirect regulators of epithelial-mesenchymal transition-mediated immunosuppression in breast carcinomas. Cancer Discov. 11, 1286\u20131305 (2021).","journal-title":"Cancer Discov."},{"key":"10212_CR6","doi-asserted-by":"publisher","unstructured":"Williams, M. M. et al. Reversing an oncogenic epithelial-to-mesenchymal transition program in breast cancer reveals actionable immune suppressive pathways. Pharmaceuticals 14. https:\/\/doi.org\/10.3390\/ph14111122 (2021).","DOI":"10.3390\/ph14111122"},{"key":"10212_CR7","doi-asserted-by":"publisher","unstructured":"Kuo, L. W. et al. Blocking tryptophan catabolism reduces triple-negative breast cancer invasive capacity. Cancer Res. Commun.. https:\/\/doi.org\/10.1158\/2767-9764.CRC-24-0272 (2024).","DOI":"10.1158\/2767-9764.CRC-24-0272"},{"key":"10212_CR8","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.ejphar.2016.06.019","volume":"788","author":"M Zhang","year":"2016","unstructured":"Zhang, M. et al. Human biliverdin reductase promotes EMT through the ERK1\/2 signal pathway in breast cancer. Eur. J. Pharm. 788, 45\u201353 (2016).","journal-title":"Eur. J. Pharm."},{"key":"10212_CR9","first-page":"1502","volume":"20","author":"SZ Shahrokhi","year":"2021","unstructured":"Shahrokhi, S. Z., Karami Tehrani, F. S. & Salami, S. Induction of cell apoptosis by biliverdin reductase inhibitor in MCF-7 and MDA-MB-468 breast cancer cell lines: experimental and in silico studies. EXCLI J. 20, 1502\u20131516 (2021).","journal-title":"EXCLI J."},{"key":"10212_CR10","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-13-516","volume":"13","author":"SJ Noh","year":"2013","unstructured":"Noh, S. J. et al. Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients. BMC Cancer 13, 516 (2013).","journal-title":"BMC Cancer"},{"key":"10212_CR11","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/nature25465","volume":"554","author":"SRV Knott","year":"2018","unstructured":"Knott, S. R. V. et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 554, 378\u2013381 (2018).","journal-title":"Nature"},{"key":"10212_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05346-7","volume":"9","author":"T Muliaditan","year":"2018","unstructured":"Muliaditan, T. et al. Macrophages are exploited from an innate wound healing response to facilitate cancer metastasis. Nat. Commun. 9, 2951 (2018).","journal-title":"Nat. Commun."},{"key":"10212_CR13","doi-asserted-by":"publisher","first-page":"473","DOI":"10.3727\/096504013X13715991125684","volume":"20","author":"R Deng","year":"2013","unstructured":"Deng, R. et al. Inhibition of tumor growth and alteration of associated macrophage cell type by an HO-1 inhibitor in breast carcinoma-bearing mice. Oncol. Res. 20, 473\u2013482 (2013).","journal-title":"Oncol. Res."},{"key":"10212_CR14","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.1158\/1078-0432.CCR-17-2587","volume":"24","author":"T Muliaditan","year":"2018","unstructured":"Muliaditan, T. et al. Repurposing tin mesoporphyrin as an immune checkpoint inhibitor shows therapeutic efficacy in preclinical models of cancer. Clin. Cancer Res. 24, 1617\u20131628 (2018).","journal-title":"Clin. Cancer Res."},{"key":"10212_CR15","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1158\/2326-6066.CIR-20-0358","volume":"9","author":"N Khojandi","year":"2021","unstructured":"Khojandi, N. et al. Oxidized lipoproteins promote resistance to cancer immunotherapy independent of patient obesity. Cancer Immunol. Res 9, 214\u2013226 (2021).","journal-title":"Cancer Immunol. Res"},{"key":"10212_CR16","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-20-0396","author":"LM Kuehm","year":"2020","unstructured":"Kuehm, L. M. et al. Fructose promotes cytoprotection in melanoma tumors and resistance to immunotherapy. Cancer Immunol. Res. https:\/\/doi.org\/10.1158\/2326-6066.CIR-20-0396 (2020).","journal-title":"Cancer Immunol. Res."},{"key":"10212_CR17","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1158\/2326-6066.CIR-13-0150","volume":"2","author":"JN Arnold","year":"2014","unstructured":"Arnold, J. N., Magiera, L., Kraman, M. & Fearon, D. T. Tumoral immune suppression by macrophages expressing fibroblast activation protein-alpha and heme oxygenase-1. Cancer Immunol. Res. 2, 121\u2013126 (2014).","journal-title":"Cancer Immunol. Res."},{"key":"10212_CR18","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/s41392-024-01769-5","volume":"9","author":"Q Zhou","year":"2024","unstructured":"Zhou, Q. et al. Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies. Signal Transduct. Target Ther. 9, 55 (2024).","journal-title":"Signal Transduct. Target Ther."},{"key":"10212_CR19","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.110661","volume":"27","author":"WD Leineweber","year":"2024","unstructured":"Leineweber, W. D. et al. Divergent iron regulatory states contribute to heterogeneity in breast cancer aggressiveness. iScience 27, 110661 (2024).","journal-title":"iScience"},{"key":"10212_CR20","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1096\/fj.03-0839fje","volume":"18","author":"K Yamashita","year":"2004","unstructured":"Yamashita, K. et al. Biliverdin, a natural product of heme catabolism, induces tolerance to cardiac allografts. FASEB J. 18, 765\u2013767 (2004).","journal-title":"FASEB J."},{"key":"10212_CR21","doi-asserted-by":"publisher","first-page":"18849","DOI":"10.1073\/pnas.1108571108","volume":"108","author":"B Wegiel","year":"2011","unstructured":"Wegiel, B. et al. Biliverdin inhibits Toll-like receptor-4 (TLR4) expression through nitric oxide-dependent nuclear translocation of biliverdin reductase. Proc. Natl. Acad. Sci. USA. 108, 18849\u201318854 (2011).","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"10212_CR22","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1542\/peds.45.1.102","volume":"45","author":"Z Nejedla","year":"1970","unstructured":"Nejedla, Z. The of immunological factors in infants with hyperbilirubinemia. development. Pediatrics 45, 102\u2013104 (1970).","journal-title":"Pediatrics"},{"key":"10212_CR23","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1002\/hep.20480","volume":"40","author":"C Fondevila","year":"2004","unstructured":"Fondevila, C. et al. Biliverdin therapy protects rat livers from ischemia and reperfusion injury. Hepatology 40, 1333\u20131341 (2004).","journal-title":"Hepatology"},{"key":"10212_CR24","doi-asserted-by":"publisher","first-page":"1468","DOI":"10.1007\/BF02088574","volume":"41","author":"Y Haga","year":"1996","unstructured":"Haga, Y., Tempero, M. A., Kay, D. & Zetterman, R. K. Intracellular accumulation of unconjugated bilirubin inhibits phytohemagglutin-induced proliferation and interleukin-2 production of human lymphocytes. Dig. Dis. Sci. 41, 1468\u20131474 (1996).","journal-title":"Dig. Dis. Sci."},{"key":"10212_CR25","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1111\/j.1699-0463.1988.tb00928.x","volume":"96","author":"V Vetvicka","year":"1988","unstructured":"Vetvicka, V. et al. Effects of bilirubin on murine peritoneal and spleen cells. APMIS 96, 671\u2013675 (1988).","journal-title":"APMIS"},{"key":"10212_CR26","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1007\/BF02927593","volume":"30","author":"V Vetvicka","year":"1985","unstructured":"Vetvicka, V., Miler, I., Sima, P., Taborsky, L. & Fornusek, L. The effect of bilirubin on the Fc receptor expression and phagocytic activity of mouse peritoneal macrophages. Folia Microbiol. 30, 373\u2013380 (1985).","journal-title":"Folia Microbiol."},{"key":"10212_CR27","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.4049\/jimmunol.181.3.1887","volume":"181","author":"Y Liu","year":"2008","unstructured":"Liu, Y. et al. Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis. J. Immunol. 181, 1887\u20131897 (2008).","journal-title":"J. Immunol."},{"key":"10212_CR28","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1002\/1097-0142(20010215)91:4<660::AID-CNCR1048>3.0.CO;2-3","volume":"91","author":"I Gurevich","year":"2001","unstructured":"Gurevich, I. & Akerley, W. Treatment of the jaundiced patient with breast carcinoma: case report and alternate therapeutic strategies. Cancer 91, 660\u2013663 (2001).","journal-title":"Cancer"},{"key":"10212_CR29","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1038\/sj.bjc.6601038","volume":"89","author":"L Wyld","year":"2003","unstructured":"Wyld, L. et al. Prognostic factors for patients with hepatic metastases from breast cancer. Br. J. Cancer 89, 284\u2013290 (2003).","journal-title":"Br. J. Cancer"},{"key":"10212_CR30","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1200\/JCO.1987.5.5.773","volume":"5","author":"JW Zinser","year":"1987","unstructured":"Zinser, J. W., Hortobagyi, G. N., Buzdar, A. U., Smith, T. L. & Fraschini, G. Clinical course of breast cancer patients with liver metastases. J. Clin. Oncol. 5, 773\u2013782 (1987).","journal-title":"J. Clin. Oncol."},{"key":"10212_CR31","unstructured":"Chauhan, P., Yadav, R., Kaushal, V. & Beniwal, P. Evaluation of serum biochemical profile of breast cancer patients. IJMRHS 5, 1\u20137 (2016)."},{"key":"10212_CR32","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/s41586-019-1007-8","volume":"567","author":"OM Rueda","year":"2019","unstructured":"Rueda, O. M. et al. Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups. Nature 567, 399\u2013404 (2019).","journal-title":"Nature"},{"key":"10212_CR33","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1038\/nature10983","volume":"486","author":"C Curtis","year":"2012","unstructured":"Curtis, C. et al. The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups. Nature 486, 346\u2013352 (2012).","journal-title":"Nature"},{"key":"10212_CR34","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11479","volume":"7","author":"B Pereira","year":"2016","unstructured":"Pereira, B. et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat. Commun. 7, 11479 (2016).","journal-title":"Nat. Commun."},{"key":"10212_CR35","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/S0021-9258(17)42488-4","volume":"261","author":"MD Maines","year":"1986","unstructured":"Maines, M. D., Trakshel, G. M. & Kutty, R. K. Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible. J. Biol. Chem. 261, 411\u2013419 (1986).","journal-title":"J. Biol. Chem."},{"key":"10212_CR36","doi-asserted-by":"publisher","first-page":"4101","DOI":"10.1016\/j.csbj.2021.07.014","volume":"19","author":"B Gyorffy","year":"2021","unstructured":"Gyorffy, B. Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer. Comput. Struct. Biotechnol. J. 19, 4101\u20134109 (2021).","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"10212_CR37","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nmeth.3337","volume":"12","author":"AM Newman","year":"2015","unstructured":"Newman, A. M. et al. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453\u2013457 (2015).","journal-title":"Nat. Methods"},{"key":"10212_CR38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1542\/peds.93.1.1","volume":"93","author":"T Valaes","year":"1994","unstructured":"Valaes, T., Petmezaki, S., Henschke, C., Drummond, G. S. & Kappas, A. Control of jaundice in preterm newborns by an inhibitor of bilirubin production: studies with tin-mesoporphyrin. Pediatrics 93, 1\u201311 (1994).","journal-title":"Pediatrics"},{"key":"10212_CR39","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1542\/peds.95.4.468","volume":"95","author":"A Kappas","year":"1995","unstructured":"Kappas, A., Drummond, G. S., Henschke, C. & Valaes, T. Direct comparison of Sn-mesoporphyrin, an inhibitor of bilirubin production, and phototherapy in controlling hyperbilirubinemia in term and near-term newborns. Pediatrics 95, 468\u2013474 (1995).","journal-title":"Pediatrics"},{"key":"10212_CR40","doi-asserted-by":"publisher","first-page":"S35","DOI":"10.1038\/jp.2010.173","volume":"31","author":"RJ Wong","year":"2011","unstructured":"Wong, R. J. et al. In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins. J. Perinatol. 31, S35\u2013S41 (2011).","journal-title":"J. Perinatol."},{"key":"10212_CR41","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.121.024424","volume":"11","author":"M Morimoto","year":"2022","unstructured":"Morimoto, M. et al. Haptoglobin regulates macrophage\/microglia-induced inflammation and prevents ischemic brain damage via binding to HMGB1. J. Am. Heart Assoc. 11, e024424 (2022).","journal-title":"J. Am. Heart Assoc."},{"key":"10212_CR42","doi-asserted-by":"publisher","first-page":"2000","DOI":"10.1016\/j.celrep.2016.04.084","volume":"15","author":"AM Georgoudaki","year":"2016","unstructured":"Georgoudaki, A. M. et al. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep. 15, 2000\u20132011 (2016).","journal-title":"Cell Rep."},{"key":"10212_CR43","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2435-y","volume":"11","author":"R Huang","year":"2020","unstructured":"Huang, R. et al. CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating beta-catenin\/STAT3 signaling. Cell Death Dis. 11, 234 (2020).","journal-title":"Cell Death Dis."},{"key":"10212_CR44","doi-asserted-by":"publisher","unstructured":"Cui, H. et al. Monocyte-derived alveolar macrophage apolipoprotein E participates in pulmonary fibrosis resolution. JCI Insight 5. https:\/\/doi.org\/10.1172\/jci.insight.134539 (2020).","DOI":"10.1172\/jci.insight.134539"},{"key":"10212_CR45","first-page":"eabj5501","volume":"7","author":"D Li","year":"2022","unstructured":"Li, D. et al. SLAMF3 and SLAMF4 are immune checkpoints that constrain macrophage phagocytosis of hematopoietic tumors. Sci. Immunol. 7, eabj5501 (2022).","journal-title":"Sci. Immunol."},{"key":"10212_CR46","doi-asserted-by":"publisher","unstructured":"Madenspacher, J. H. et al. Cholesterol 25-hydroxylase promotes efferocytosis and resolution of lung inflammation. JCI Insight 5. https:\/\/doi.org\/10.1172\/jci.insight.137189 (2020).","DOI":"10.1172\/jci.insight.137189"},{"key":"10212_CR47","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2021.2024941","volume":"11","author":"J Lin","year":"2022","unstructured":"Lin, J. et al. MerTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and PD-L1 expression. Oncoimmunology 11, 2024941 (2022).","journal-title":"Oncoimmunology"},{"key":"10212_CR48","doi-asserted-by":"publisher","first-page":"4705","DOI":"10.1016\/S0021-9258(17)37600-7","volume":"269","author":"QW Xie","year":"1994","unstructured":"Xie, Q. W., Kashiwabara, Y. & Nathan, C. Role of transcription factor NF-kappa B\/Rel in induction of nitric oxide synthase. J. Biol. Chem. 269, 4705\u20134708 (1994).","journal-title":"J. Biol. Chem."},{"key":"10212_CR49","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.molmet.2015.07.005","volume":"4","author":"AA Hill","year":"2015","unstructured":"Hill, A. A. et al. Activation of NF-kappaB drives the enhanced survival of adipose tissue macrophages in an obesogenic environment. Mol. Metab. 4, 665\u2013677 (2015).","journal-title":"Mol. Metab."},{"key":"10212_CR50","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1002\/1878-0261.12616","volume":"14","author":"A Arlt","year":"2020","unstructured":"Arlt, A. et al. High CD206 levels in Hodgkin lymphoma-educated macrophages are linked to matrix-remodeling and lymphoma dissemination. Mol. Oncol. 14, 571\u2013589 (2020).","journal-title":"Mol. Oncol."},{"key":"10212_CR51","doi-asserted-by":"publisher","first-page":"22039","DOI":"10.1074\/jbc.M312735200","volume":"279","author":"KM Khan","year":"2004","unstructured":"Khan, K. M., Howe, L. R. & Falcone, D. J. Extracellular matrix-induced cyclooxygenase-2 regulates macrophage proteinase expression. J. Biol. Chem. 279, 22039\u201322046 (2004).","journal-title":"J. Biol. Chem."},{"key":"10212_CR52","doi-asserted-by":"publisher","first-page":"29637","DOI":"10.18632\/oncotarget.4936","volume":"6","author":"H Li","year":"2015","unstructured":"Li, H. et al. Cyclooxygenase-2 in tumor-associated macrophages promotes breast cancer cell survival by triggering a positive-feedback loop between macrophages and cancer cells. Oncotarget 6, 29637\u201329650 (2015).","journal-title":"Oncotarget"},{"key":"10212_CR53","doi-asserted-by":"publisher","first-page":"e63451","DOI":"10.1371\/journal.pone.0063451","volume":"8","author":"YR Na","year":"2013","unstructured":"Na, Y. R., Yoon, Y. N., Son, D. I. & Seok, S. H. Cyclooxygenase-2 inhibition blocks M2 macrophage differentiation and suppresses metastasis in murine breast cancer model. PLoS One 8, e63451 (2013).","journal-title":"PLoS One"},{"key":"10212_CR54","doi-asserted-by":"publisher","unstructured":"Alaluf, E. et al. Heme oxygenase-1 orchestrates the immunosuppressive program of tumor-associated macrophages. JCI Insight 5. https:\/\/doi.org\/10.1172\/jci.insight.133929 (2020).","DOI":"10.1172\/jci.insight.133929"},{"key":"10212_CR55","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.1016\/j.devcel.2023.06.006","volume":"58","author":"JE Anstee","year":"2023","unstructured":"Anstee, J. E. et al. LYVE-1(+) macrophages form a collaborative CCR5-dependent perivascular niche that influences chemotherapy responses in murine breast cancer. Dev. Cell 58, 1548\u20131561 e1510 (2023).","journal-title":"Dev. Cell"},{"key":"10212_CR56","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.ads3085","volume":"17","author":"M Bahri","year":"2025","unstructured":"Bahri, M. et al. An oral heme oxygenase inhibitor targets immunosuppressive perivascular macrophages in preclinical models of cancer. Sci. Transl. Med. 17, eads3085 (2025).","journal-title":"Sci. Transl. Med."},{"key":"10212_CR57","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1158\/2767-9764.CRC-22-0043","volume":"2","author":"A Lepland","year":"2022","unstructured":"Lepland, A. et al. Depletion of mannose receptor-positive tumor-associated macrophages via a peptide-targeted star-shaped polyglutamate inhibits breast cancer progression in mice. Cancer Res. Commun. 2, 533\u2013551 (2022).","journal-title":"Cancer Res. Commun."},{"key":"10212_CR58","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02481-5","volume":"9","author":"N Linde","year":"2018","unstructured":"Linde, N. et al. Macrophages orchestrate breast cancer early dissemination and metastasis. Nat. Commun. 9, 21 (2018).","journal-title":"Nat. Commun."},{"key":"10212_CR59","doi-asserted-by":"publisher","unstructured":"Fang, J. et al. Expression dynamics of heme oxygenase-1 in tumor cells and the host contributes to the progression of tumors. J. Pers. Med. 11. https:\/\/doi.org\/10.3390\/jpm11121340 (2021).","DOI":"10.3390\/jpm11121340"},{"key":"10212_CR60","doi-asserted-by":"publisher","unstructured":"Was, H. et al. Effect of heme oxygenase-1 on melanoma development in mice-role of tumor-infiltrating immune cells. Antioxidants 9. https:\/\/doi.org\/10.3390\/antiox9121223 (2020).","DOI":"10.3390\/antiox9121223"},{"key":"10212_CR61","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1158\/1535-7163.MCT-07-2199","volume":"7","author":"CW Lin","year":"2008","unstructured":"Lin, C. W., Shen, S. C., Hou, W. C., Yang, L. Y. & Chen, Y. C. Heme oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9. Mol. Cancer Ther. 7, 1195\u20131206 (2008).","journal-title":"Mol. Cancer Ther."},{"key":"10212_CR62","doi-asserted-by":"publisher","first-page":"2030","DOI":"10.1089\/ars.2018.7554","volume":"30","author":"NA Gandini","year":"2019","unstructured":"Gandini, N. A. et al. Heme oxygenase-1 Has an antitumor role in breast cancer. Antioxid. Redox Signal 30, 2030\u20132049 (2019).","journal-title":"Antioxid. Redox Signal"},{"key":"10212_CR63","doi-asserted-by":"publisher","unstructured":"Chang, H. L., Schwettmann, B., McArthur, H. L. & Chan, I. S. Antibody-drug conjugates in breast cancer: overcoming resistance and boosting immune response. J. Clin. Investig. 133. https:\/\/doi.org\/10.1172\/JCI172156 (2023).","DOI":"10.1172\/JCI172156"},{"key":"10212_CR64","doi-asserted-by":"publisher","first-page":"4744","DOI":"10.4049\/jimmunol.172.8.4744","volume":"172","author":"HO Pae","year":"2004","unstructured":"Pae, H. O. et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J. Immunol. 172, 4744\u20134751 (2004).","journal-title":"J. Immunol."},{"key":"10212_CR65","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1189\/jlb.0508280","volume":"87","author":"M Biburger","year":"2010","unstructured":"Biburger, M., Theiner, G., Schadle, M., Schuler, G. & Tiegs, G. Pivotal Advance: Heme oxygenase 1 expression by human CD4+ T cells is not sufficient for their development of immunoregulatory capacity. J. Leukoc. Biol. 87, 193\u2013202 (2010).","journal-title":"J. Leukoc. Biol."},{"key":"10212_CR66","doi-asserted-by":"publisher","unstructured":"Porte, S. et al. Iron boosts anti-tumor type 1 T-cell responses and anti-PD1 immunotherapy. Cancer Immunol. Res.. https:\/\/doi.org\/10.1158\/2326-6066.CIR-23-0739 (2024).","DOI":"10.1158\/2326-6066.CIR-23-0739"},{"key":"10212_CR67","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1016\/j.cell.2018.09.030","volume":"175","author":"MM Gubin","year":"2018","unstructured":"Gubin, M. M. et al. High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy. Cell 175, 1014\u20131030 e1019 (2018).","journal-title":"Cell"},{"key":"10212_CR68","doi-asserted-by":"publisher","first-page":"ra116","DOI":"10.1126\/scitranslmed.3006504","volume":"5","author":"S Spranger","year":"2013","unstructured":"Spranger, S. et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci. Transl. Med. 5, ra116 (2013).","journal-title":"Sci. Transl. Med."},{"key":"10212_CR69","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111776","volume":"140","author":"A Tajbakhsh","year":"2021","unstructured":"Tajbakhsh, A. et al. The complex roles of efferocytosis in cancer development, metastasis, and treatment. Biomed. Pharmacother. 140, 111776 (2021).","journal-title":"Biomed. Pharmacother."},{"key":"10212_CR70","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.ccell.2016.06.005","volume":"30","author":"S Di Biase","year":"2016","unstructured":"Di Biase, S. et al. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136\u2013146 (2016).","journal-title":"Cancer Cell"},{"key":"10212_CR71","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1111\/j.1471-4159.2006.03680.x","volume":"96","author":"A Fernandes","year":"2006","unstructured":"Fernandes, A. et al. Inflammatory signalling pathways involved in astroglial activation by unconjugated bilirubin. J. Neurochem 96, 1667\u20131679 (2006).","journal-title":"J. Neurochem"},{"key":"10212_CR72","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106520","volume":"84","author":"Y Li","year":"2020","unstructured":"Li, Y. et al. Physiological concentrations of bilirubin control inflammatory response by inhibiting NF-kappaB and inflammasome activation. Int. Immunopharmacol. 84, 106520 (2020).","journal-title":"Int. Immunopharmacol."},{"key":"10212_CR73","doi-asserted-by":"publisher","unstructured":"Adapa, S. R. et al. Porphyrin overdrive rewires cancer cell metabolism. Life Sci. Alliance 7. https:\/\/doi.org\/10.26508\/lsa.202302547 (2024).","DOI":"10.26508\/lsa.202302547"},{"key":"10212_CR74","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.3427","volume":"9","author":"MR Sullivan","year":"2019","unstructured":"Sullivan, M. R., Lewis, C. A. & Muir, A. Isolation and quantification of metabolite levels in murine tumor interstitial fluid by LC\/MS. Bio Protoc. 9, e3427 (2019).","journal-title":"Bio Protoc."},{"key":"10212_CR75","doi-asserted-by":"publisher","unstructured":"Amend, S. R., Valkenburg, K. C. & Pienta, K. J. Murine hind limb long bone dissection and bone marrow isolation. J. Vis. Exp.. https:\/\/doi.org\/10.3791\/53936 (2016).","DOI":"10.3791\/53936"},{"key":"10212_CR76","doi-asserted-by":"crossref","unstructured":"Ewels, P. A. et al. The nf-core framework for community-curated bioinformatics pipelines. Nat. Biotechnol. 38, 276\u2013278 (2020).","DOI":"10.1038\/s41587-020-0439-x"},{"key":"10212_CR77","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1089\/cmb.2017.0096","volume":"24","author":"A Kechin","year":"2017","unstructured":"Kechin, A., Boyarskikh, U., Kel, A. & Filipenko, M. cutPrimers: a new tool for accurate cutting of primers from reads of targeted next generation sequencing. J. Comput Biol. 24, 1138\u20131143 (2017).","journal-title":"J. Comput Biol."},{"key":"10212_CR78","doi-asserted-by":"publisher","unstructured":"Krueger, F., James, F., Ewels, P., Afyounian, E., Weinstein, M. FelixKrueger\/TrimGalore: v0.6.10 - add default decompression path. https:\/\/doi.org\/10.5281\/zenodo.7598955 (2023).","DOI":"10.5281\/zenodo.7598955"},{"key":"10212_CR79","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15\u201321 (2013).","journal-title":"Bioinformatics"},{"key":"10212_CR80","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/nmeth.4197","volume":"14","author":"R Patro","year":"2017","unstructured":"Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417\u2013419 (2017).","journal-title":"Nat. Methods"},{"key":"10212_CR81","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.12688\/f1000research.7563.1","volume":"4","author":"C Soneson","year":"2015","unstructured":"Soneson, C., Love, M. I. & Robinson, M. D. Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. F1000Research 4, 1521 (2015).","journal-title":"F1000Research"},{"key":"10212_CR82","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2010","unstructured":"Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139\u2013140 (2010).","journal-title":"Bioinformatics"},{"key":"10212_CR83","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).","journal-title":"Nucleic Acids Res."},{"key":"10212_CR84","doi-asserted-by":"publisher","unstructured":"Korotkevich, G., Sukhov, V. & Sergushichev, A. Fast gene set enrichment analysis. Preprint at: https:\/\/doi.org\/10.1101\/060012 (2019).","DOI":"10.1101\/060012"},{"key":"10212_CR85","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","volume":"27","author":"A Liberzon","year":"2011","unstructured":"Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739\u20131740 (2011).","journal-title":"Bioinformatics"},{"key":"10212_CR86","unstructured":"Dolgalev, I. msigdbr: MSigDB Gene Sets for Multiple Organisms in a Tidy Data Format (2025)."},{"key":"10212_CR87","doi-asserted-by":"publisher","first-page":"W216","DOI":"10.1093\/nar\/gkac194","volume":"50","author":"BT Sherman","year":"2022","unstructured":"Sherman, B. T. et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 50, W216\u2013W221 (2022).","journal-title":"Nucleic Acids Res."},{"key":"10212_CR88","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nprot.2008.211","volume":"4","author":"W Huang da","year":"2009","unstructured":"Huang da, W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44\u201357 (2009).","journal-title":"Nat. Protoc."},{"key":"10212_CR89","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1038\/nmeth.4463","volume":"14","author":"S Aibar","year":"2017","unstructured":"Aibar, S. et al. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083\u20131086 (2017).","journal-title":"Nat. Methods"},{"key":"10212_CR90","unstructured":"Williams, M. M. (figshare, 2026)."},{"key":"10212_CR91","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/nar\/30.1.207","volume":"30","author":"R Edgar","year":"2002","unstructured":"Edgar, R., Domrachev, M. & Lash, A. E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207\u2013210 (2002).","journal-title":"Nucleic Acids Res."},{"key":"10212_CR92","doi-asserted-by":"publisher","first-page":"D640","DOI":"10.1093\/nar\/gkad1045","volume":"52","author":"O Yurekten","year":"2024","unstructured":"Yurekten, O. et al. MetaboLights: open data repository for metabolomics. Nucleic Acids Res. 52, D640\u2013D646 (2024).","journal-title":"Nucleic Acids Res."}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10212-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10212-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10212-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T11:03:01Z","timestamp":1784286181000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10212-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,9]]},"references-count":92,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["10212"],"URL":"https:\/\/doi.org\/10.1038\/s42003-026-10212-0","relation":{},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,9]]},"assertion":[{"value":"19 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"977"}}