{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T19:22:43Z","timestamp":1792264963105,"version":"4.4.0"},"reference-count":82,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T00:00:00Z","timestamp":1714348800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T00:00:00Z","timestamp":1714348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81773233"],"award-info":[{"award-number":["81773233"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273323"],"award-info":[{"award-number":["82273323"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Exp Clin Cancer Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Brain metastasis is one of the main causes of recurrence and death in non-small cell lung cancer (NSCLC). Although radiotherapy is the main local therapy for brain metastasis, it is inevitable that some cancer cells become resistant to radiation. Microglia, as macrophages colonized in the brain, play an important role in the tumor microenvironment. Radiotherapy could activate microglia to polarize into both the M1 and M2 phenotypes. Therefore, searching for crosstalk molecules within the microenvironment that can specifically regulate the polarization of microglia is a potential strategy for improving radiation resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used databases to detect the expression of MIF in NSCLC and its relationship with prognosis. We analyzed the effects of targeted blockade of the MIF\/CD74 axis on the polarization and function of microglia during radiotherapy using flow cytometry. The mouse model of brain metastasis was used to assess the effect of targeted blockade of MIF\/CD74 axis on the growth of brain metastasis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>Our findings reveals that the macrophage migration inhibitory factor (MIF) was highly expressed in NSCLC and is associated with the prognosis of NSCLC. Mechanistically, we demonstrated CD74 inhibition reversed radiation-induced AKT phosphorylation in microglia and promoted the M1 polarization in combination of radiation. Additionally, blocking the MIF-CD74 interaction between NSCLC and microglia promoted microglia M1 polarization. Furthermore, radiation improved tumor hypoxia to decrease HIF-1\u03b1 dependent MIF secretion by NSCLC. MIF inhibition enhanced radiosensitivity for brain metastasis via synergistically promoting microglia M1 polarization in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study revealed that targeting the MIF-CD74 axis promoted microglia M1 polarization and synergized with radiotherapy for brain metastasis in NSCLC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-024-03024-9","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T09:03:32Z","timestamp":1714381412000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Blocking the MIF-CD74 axis augments radiotherapy efficacy for brain metastasis in NSCLC via synergistically promoting microglia M1 polarization"],"prefix":"10.1186","volume":"43","author":[{"given":"Lichao","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingjuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawen","family":"Bin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiguang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaorong","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,29]]},"reference":[{"issue":"1","key":"3024_CR1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3322\/caac.21763","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17\u201348.","journal-title":"CA Cancer J Clin"},{"issue":"4","key":"3024_CR2","doi-asserted-by":"publisher","first-page":"e373","DOI":"10.1016\/j.cllc.2018.01.007","volume":"19","author":"SN Waqar","year":"2018","unstructured":"Waqar SN, Samson PP, Robinson CG, Bradley J, Devarakonda S, Du L, et al. Non-small-cell Lung Cancer With Brain Metastasis at Presentation. Clin Lung Cancer. 2018;19(4):e373\u20139.","journal-title":"Clin Lung Cancer"},{"issue":"5","key":"3024_CR3","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1200\/JCO.21.02314","volume":"40","author":"MA Vogelbaum","year":"2022","unstructured":"Vogelbaum MA, Brown PD, Messersmith H, Brastianos PK, Burri S, Cahill D, et al. Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline. J Clin Oncol. 2022;40(5):492\u2013516.","journal-title":"J Clin Oncol"},{"key":"3024_CR4","doi-asserted-by":"publisher","first-page":"1131874","DOI":"10.3389\/fimmu.2023.1131874","volume":"14","author":"IM Khan","year":"2023","unstructured":"Khan IM, Khan SU, Sala HSS, Khan MU, Ud Din MA, Khan S, et al. TME-targeted approaches of brain metastases and its clinical therapeutic evidence. Front Immunol. 2023;14:1131874.","journal-title":"Front Immunol"},{"issue":"8","key":"3024_CR5","doi-asserted-by":"publisher","first-page":"2101","DOI":"10.1158\/0008-5472.CAN-20-1785","volume":"81","author":"TJ Berg","year":"2021","unstructured":"Berg TJ, Marques C, Pantazopoulou V, Johansson E, von Stedingk K, Lindgren D, et al. The Irradiated Brain Microenvironment Supports Glioma Stemness and Survival via Astrocyte-Derived Transglutaminase 2. Can Res. 2021;81(8):2101\u201315.","journal-title":"Can Res"},{"issue":"3","key":"3024_CR6","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.ccell.2017.02.009","volume":"31","author":"DF Quail","year":"2017","unstructured":"Quail DF, Joyce JA. The Microenvironmental Landscape of Brain Tumors. Cancer Cell. 2017;31(3):326\u201341.","journal-title":"Cancer Cell"},{"issue":"1","key":"3024_CR7","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/s41392-022-00872-9","volume":"7","author":"Y Jin","year":"2022","unstructured":"Jin Y, Kang Y, Wang M, Wu B, Su B, Yin H, et al. Targeting polarized phenotype of microglia via IL6\/JAK2\/STAT3 signaling to reduce NSCLC brain metastasis. Signal Transduct Target Ther. 2022;7(1):52.","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"3024_CR8","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/nn.4185","volume":"19","author":"D Hambardzumyan","year":"2016","unstructured":"Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016;19(1):20\u20137.","journal-title":"Nat Neurosci"},{"issue":"1","key":"3024_CR9","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13058-022-01514-2","volume":"24","author":"SL Foo","year":"2022","unstructured":"Foo SL, Sachaphibulkij K, Lee CLY, Yap GLR, Cui J, Arumugam T, et al. Breast cancer metastasis to brain results in recruitment and activation of microglia through annexin-A1\/formyl peptide receptor signaling. Breast cancer research\u202f: BCR. 2022;24(1):25.","journal-title":"Breast cancer research : BCR"},{"key":"3024_CR10","doi-asserted-by":"publisher","unstructured":"Khan F, Pang L, Dunterman M, Lesniak MS, Heimberger AB, Chen P. Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy. The Journal of clinical investigation. 2023;133(1). https:\/\/doi.org\/10.1172\/JCI163446.","DOI":"10.1172\/JCI163446"},{"issue":"4","key":"3024_CR11","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.it.2021.02.004","volume":"42","author":"W Xuan","year":"2021","unstructured":"Xuan W, Lesniak MS, James CD, Heimberger AB, Chen P. Context-Dependent Glioblastoma-Macrophage\/Microglia Symbiosis and Associated Mechanisms. Trends Immunol. 2021;42(4):280\u201392.","journal-title":"Trends Immunol"},{"key":"3024_CR12","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.114354","volume":"183","author":"N Cheng","year":"2021","unstructured":"Cheng N, Bai X, Shu Y, Ahmad O, Shen P. Targeting tumor-associated macrophages as an antitumor strategy. Biochem Pharmacol. 2021;183: 114354.","journal-title":"Biochem Pharmacol"},{"issue":"12","key":"3024_CR13","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.it.2004.09.015","volume":"25","author":"A Mantovani","year":"2004","unstructured":"Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677\u201386.","journal-title":"Trends Immunol"},{"issue":"9","key":"3024_CR14","doi-asserted-by":"publisher","first-page":"6425","DOI":"10.1002\/jcp.26429","volume":"233","author":"A Shapouri-Moghaddam","year":"2018","unstructured":"Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018;233(9):6425\u201340.","journal-title":"J Cell Physiol"},{"issue":"5","key":"3024_CR15","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1007\/s00401-015-1482-4","volume":"130","author":"P Chen","year":"2015","unstructured":"Chen P, Piao X, Bonaldo P. Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury. Acta Neuropathol. 2015;130(5):605\u201318.","journal-title":"Acta Neuropathol"},{"issue":"1","key":"3024_CR16","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s13045-019-0760-3","volume":"12","author":"Y Lin","year":"2019","unstructured":"Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol. 2019;12(1):76.","journal-title":"J Hematol Oncol"},{"issue":"7\u20139","key":"3024_CR17","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1387\/ijdb.113371dl","volume":"55","author":"D Laoui","year":"2011","unstructured":"Laoui D, Movahedi K, Van Overmeire E, Van den Bossche J, Schouppe E, Mommer C, et al. Tumor-associated macrophages in breast cancer: distinct subsets, distinct functions. Int J Dev Biol. 2011;55(7\u20139):861\u20137.","journal-title":"Int J Dev Biol"},{"issue":"11","key":"3024_CR18","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/S1471-4906(02)02302-5","volume":"23","author":"A Mantovani","year":"2002","unstructured":"Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549\u201355.","journal-title":"Trends Immunol"},{"issue":"10","key":"3024_CR19","doi-asserted-by":"publisher","first-page":"3672","DOI":"10.1172\/JCI84427","volume":"126","author":"AT Henze","year":"2016","unstructured":"Henze AT, Mazzone M. The impact of hypoxia on tumor-associated macrophages. J Clin Investig. 2016;126(10):3672\u20139.","journal-title":"J Clin Investig"},{"key":"3024_CR20","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/1757-2215-7-19","volume":"7","author":"M Zhang","year":"2014","unstructured":"Zhang M, He Y, Sun X, Li Q, Wang W, Zhao A, et al. A high M1\/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. J Ovarian Res. 2014;7:19.","journal-title":"J Ovarian Res"},{"issue":"4","key":"3024_CR21","doi-asserted-by":"publisher","first-page":"e626","DOI":"10.1097\/SLA.0000000000004037","volume":"275","author":"H Zhang","year":"2022","unstructured":"Zhang H, Li R, Cao Y, Gu Y, Lin C, Liu X, et al. Poor Clinical Outcomes and Immunoevasive Contexture in Intratumoral IL-10-Producing Macrophages Enriched Gastric Cancer Patients. Ann Surg. 2022;275(4):e626\u201335.","journal-title":"Ann Surg"},{"key":"3024_CR22","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.trsl.2022.06.003","volume":"248","author":"P Luo","year":"2022","unstructured":"Luo P, Lednovich K, Xu K, Nnyamah C, Layden BT, Xu P. Central and peripheral regulations mediated by short-chain fatty acids on energy homeostasis. Transl Res. 2022;248:128\u201350.","journal-title":"Transl Res"},{"issue":"6","key":"3024_CR23","doi-asserted-by":"publisher","first-page":"2067","DOI":"10.1016\/j.ymthe.2021.02.016","volume":"29","author":"J Ning","year":"2021","unstructured":"Ning J, Ye Y, Bu D, Zhao G, Song T, Liu P, et al. Imbalance of TGF-\u03b21\/BMP-7 pathways induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness. Mol Ther. 2021;29(6):2067\u201387.","journal-title":"Mol Ther"},{"key":"3024_CR24","doi-asserted-by":"publisher","unstructured":"Jarosz-Biej M, Smolarczyk R, Cicho\u0144 T, Ku\u0142ach N. Tumor Microenvironment as A \"Game Changer\" in Cancer Radiotherapy. International journal of molecular sciences. 2019;20(13). https:\/\/doi.org\/10.3390\/ijms20133212.","DOI":"10.3390\/ijms20133212"},{"issue":"4","key":"3024_CR25","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.bj.2017.07.001","volume":"40","author":"EL Walton","year":"2017","unstructured":"Walton EL. Radiotherapy and the tumor microenvironment: The \u201cmacro\u201d picture. Biomed J. 2017;40(4):185\u20138.","journal-title":"Biomed J"},{"issue":"4","key":"3024_CR26","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.bj.2017.06.003","volume":"40","author":"Q Wu","year":"2017","unstructured":"Wu Q, Allouch A, Martins I, Modjtahedi N, Deutsch E, Perfettini JL. Macrophage biology plays a central role during ionizing radiation-elicited tumor response. Biomed J. 2017;40(4):200\u201311.","journal-title":"Biomed J"},{"key":"3024_CR27","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/281958","volume":"2013","author":"MJ Gough","year":"2013","unstructured":"Gough MJ, Young K, Crittenden M. The impact of the myeloid response to radiation therapy. Clin Dev Immunol. 2013;2013: 281958.","journal-title":"Clin Dev Immunol"},{"issue":"11","key":"3024_CR28","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1080\/09553000500531886","volume":"81","author":"R Pandey","year":"2005","unstructured":"Pandey R, Shankar BS, Sharma D, Sainis KB. Low dose radiation induced immunomodulation: effect on macrophages and CD8+ T cells. Int J Radiat Biol. 2005;81(11):801\u201312.","journal-title":"Int J Radiat Biol"},{"issue":"6","key":"3024_CR29","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1016\/S0891-5849(96)00500-X","volume":"22","author":"Y Ibuki","year":"1997","unstructured":"Ibuki Y, Goto R. Enhancement of NO production from resident peritoneal macrophages by in vitro gamma-irradiation and its relationship to reactive oxygen intermediates. Free Rad Biol Med. 1997;22(6):1029\u201335.","journal-title":"Free Rad Biol Med"},{"key":"3024_CR30","doi-asserted-by":"publisher","unstructured":"Wang SJ, Haffty B. Radiotherapy as a New Player in Immuno-Oncology. Cancers. 2018;10(12). https:\/\/doi.org\/10.3390\/cancers10120515.","DOI":"10.3390\/cancers10120515"},{"issue":"2","key":"3024_CR31","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.ijrobp.2007.01.041","volume":"68","author":"CS Tsai","year":"2007","unstructured":"Tsai CS, Chen FH, Wang CC, Huang HL, Jung SM, Wu CJ, et al. Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth. Int J Radiat Oncol Biol Phys. 2007;68(2):499\u2013507.","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"3024_CR32","doi-asserted-by":"publisher","first-page":"89","DOI":"10.3389\/fonc.2012.00089","volume":"2","author":"CS Chiang","year":"2012","unstructured":"Chiang CS, Fu SY, Wang SC, Yu CF, Chen FH, Lin CM, et al. Irradiation promotes an m2 macrophage phenotype in tumor hypoxia. Front Oncol. 2012;2:89.","journal-title":"Front Oncol"},{"issue":"9","key":"3024_CR33","doi-asserted-by":"publisher","first-page":"2782","DOI":"10.1158\/0008-5472.CAN-12-3981","volume":"73","author":"J Xu","year":"2013","unstructured":"Xu J, Escamilla J, Mok S, David J, Priceman S, West B, et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Can Res. 2013;73(9):2782\u201394.","journal-title":"Can Res"},{"issue":"1","key":"3024_CR34","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s12929-019-0568-z","volume":"26","author":"Y Chen","year":"2019","unstructured":"Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z. Tumor-associated macrophages: an accomplice in solid tumor progression. J Biomed Sci. 2019;26(1):78.","journal-title":"J Biomed Sci"},{"issue":"5","key":"3024_CR35","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1158\/2326-6066.CIR-14-0232","volume":"3","author":"SL Shiao","year":"2015","unstructured":"Shiao SL, Ruffell B, DeNardo DG, Faddegon BA, Park CC, Coussens LM. TH2-Polarized CD4(+) T Cells and Macrophages Limit Efficacy of Radiotherapy. Cancer Immunol Res. 2015;3(5):518\u201325.","journal-title":"Cancer Immunol Res"},{"key":"3024_CR36","doi-asserted-by":"publisher","unstructured":"Song L, Sun Q, Zheng H, Zhang Y, Wang Y, Liu S, et al. Roseburia hominis Alleviates Neuroinflammation via Short-Chain Fatty Acids through Histone Deacetylase Inhibition. Molecular nutrition & food research. 2022:e2200164. https:\/\/doi.org\/10.1002\/mnfr.202200164.","DOI":"10.1002\/mnfr.202200164"},{"issue":"20","key":"3024_CR37","doi-asserted-by":"publisher","first-page":"5510","DOI":"10.1158\/1078-0432.CCR-21-0810","volume":"27","author":"CC Foster","year":"2021","unstructured":"Foster CC, Fleming GF, Karrison TG, Liao CY, Desai AV, Moroney JW, et al. Phase I Study of Stereotactic Body Radiotherapy plus Nivolumab and Urelumab or Cabiralizumab in Advanced Solid Tumors. Clin Cancer Res. 2021;27(20):5510\u20138.","journal-title":"Clin Cancer Res"},{"key":"3024_CR38","doi-asserted-by":"publisher","unstructured":"Malfitano AM, Pisanti S, Napolitano F, Di Somma S, Martinelli R, Portella G. Tumor-Associated Macrophage Status in Cancer Treatment. Cancers. 2020;12(7). https:\/\/doi.org\/10.3390\/cancers12071987.","DOI":"10.3390\/cancers12071987"},{"issue":"2","key":"3024_CR39","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2020.100983","volume":"14","author":"AI Younes","year":"2021","unstructured":"Younes AI, Barsoumian HB, Sezen D, Verma V, Patel R, Wasley M, et al. Addition of TLR9 agonist immunotherapy to radiation improves systemic antitumor activity. Transl Oncol. 2021;14(2): 100983.","journal-title":"Transl Oncol"},{"issue":"2","key":"3024_CR40","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1182\/blood-2011-05-355222","volume":"119","author":"YH Kim","year":"2012","unstructured":"Kim YH, Gratzinger D, Harrison C, Brody JD, Czerwinski DK, Ai WZ, et al. In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1\/2 study. Blood. 2012;119(2):355\u201363.","journal-title":"Blood"},{"issue":"2","key":"3024_CR41","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1007\/s12253-016-0138-6","volume":"23","author":"CC Nobre","year":"2017","unstructured":"Nobre CC, de Ara\u00fajo JM, Fernandes TA, Cobucci RN, Lanza DC, Andrade VS, et al. Macrophage Migration Inhibitory Factor (MIF): Biological Activities and Relation with Cancer. Pathol Oncol Res. 2017;23(2):235\u201344.","journal-title":"Pathol Oncol Res"},{"issue":"2","key":"3024_CR42","doi-asserted-by":"publisher","first-page":"523","DOI":"10.3892\/or.2014.3272","volume":"32","author":"V Richard","year":"2014","unstructured":"Richard V, Kindt N, Decaestecker C, Gabius HJ, Laurent G, No\u00ebl JC, et al. Involvement of macrophage migration inhibitory factor and its receptor (CD74) in human breast cancer. Oncol Rep. 2014;32(2):523\u20139.","journal-title":"Oncol Rep"},{"issue":"5","key":"3024_CR43","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202001605R","volume":"35","author":"A Ives","year":"2021","unstructured":"Ives A, Le Roy D, Th\u00e9roude C, Bernhagen J, Roger T, Calandra T. Macrophage migration inhibitory factor promotes the migration of dendritic cells through CD74 and the activation of the Src\/PI3K\/myosin II pathway. FASEB J. 2021;35(5): e21418.","journal-title":"FASEB J"},{"issue":"2","key":"3024_CR44","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/s41419-022-04552-y","volume":"13","author":"Y Fukuda","year":"2022","unstructured":"Fukuda Y, Bustos MA, Cho SN, Roszik J, Ryu S, Lopez VM, et al. Interplay between soluble CD74 and macrophage-migration inhibitory factor drives tumor growth and influences patient survival in melanoma. Cell Death Dis. 2022;13(2):117.","journal-title":"Cell Death Dis"},{"issue":"3","key":"3024_CR45","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1007\/s00011-016-0995-1","volume":"66","author":"H Su","year":"2017","unstructured":"Su H, Na N, Zhang X, Zhao Y. The biological function and significance of CD74 in immune diseases. Inflamm Res. 2017;66(3):209\u201316.","journal-title":"Inflamm Res"},{"issue":"1","key":"3024_CR46","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s13046-016-0475-z","volume":"36","author":"F Bozzi","year":"2017","unstructured":"Bozzi F, Mogavero A, Varinelli L, Belfiore A, Manenti G, Caccia C, et al. MIF\/CD74 axis is a target for novel therapies in colon carcinomatosis. J Exp Clin Cancer Res. 2017;36(1):16.","journal-title":"J Exp Clin Cancer Res"},{"issue":"1","key":"3024_CR47","doi-asserted-by":"publisher","first-page":"1846915","DOI":"10.1080\/2162402X.2020.1846915","volume":"9","author":"RA de Azevedo","year":"2020","unstructured":"de Azevedo RA, Shoshan E, Whang S, Markel G, Jaiswal AR, Liu A, et al. MIF inhibition as a strategy for overcoming resistance to immune checkpoint blockade therapy in melanoma. Oncoimmunology. 2020;9(1):1846915.","journal-title":"Oncoimmunology"},{"issue":"9","key":"3024_CR48","doi-asserted-by":"publisher","first-page":"2813","DOI":"10.1158\/0008-5472.CAN-15-1011","volume":"76","author":"R Fukaya","year":"2016","unstructured":"Fukaya R, Ohta S, Yaguchi T, Matsuzaki Y, Sugihara E, Okano H, et al. MIF Maintains the Tumorigenic Capacity of Brain Tumor-Initiating Cells by Directly Inhibiting p53. Can Res. 2016;76(9):2813\u201323.","journal-title":"Can Res"},{"issue":"14","key":"3024_CR49","first-page":"7690","volume":"24","author":"Y Luo","year":"2020","unstructured":"Luo Y, Hou WT, Zeng L, Li ZP, Ge W, Yi C, et al. Progress in the study of markers related to glioma prognosis. Eur Rev Med Pharmacol Sci. 2020;24(14):7690\u20137.","journal-title":"Eur Rev Med Pharmacol Sci"},{"issue":"1","key":"3024_CR50","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s10585-010-9354-8","volume":"28","author":"T Seike","year":"2011","unstructured":"Seike T, Fujita K, Yamakawa Y, Kido MA, Takiguchi S, Teramoto N, et al. Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis. Clin Exp Metas. 2011;28(1):13\u201325.","journal-title":"Clin Exp Metas"},{"issue":"1","key":"3024_CR51","first-page":"14","volume":"44","author":"R Eguchi","year":"2020","unstructured":"Eguchi R, Wakabayashi I. HDGF enhances VEGF-dependent angiogenesis and FGF-2 is a VEGF-independent angiogenic factor in non-small cell lung cancer. Oncol Rep. 2020;44(1):14\u201328.","journal-title":"Oncol Rep"},{"key":"3024_CR52","doi-asserted-by":"publisher","unstructured":"Jeong H, Lee SY, Seo H, Kim BJ. Recombinant Mycobacterium smegmatis delivering a fusion protein of human macrophage migration inhibitory factor (MIF) and IL-7 exerts an anticancer effect by inducing an immune response against MIF in a tumor-bearing mouse model. Journal for immunotherapy of cancer. 2021;9(8). https:\/\/doi.org\/10.1136\/jitc-2021-003180.","DOI":"10.1136\/jitc-2021-003180"},{"issue":"3","key":"3024_CR53","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1111\/j.1582-4934.2010.01041.x","volume":"15","author":"D Simons","year":"2011","unstructured":"Simons D, Grieb G, Hristov M, Pallua N, Weber C, Bernhagen J, et al. Hypoxia-induced endothelial secretion of macrophage migration inhibitory factor and role in endothelial progenitor cell recruitment. J Cell Mol Med. 2011;15(3):668\u201378.","journal-title":"J Cell Mol Med"},{"issue":"1","key":"3024_CR54","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1158\/0008-5472.CAN-06-3292","volume":"67","author":"M Winner","year":"2007","unstructured":"Winner M, Koong AC, Rendon BE, Zundel W, Mitchell RA. Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization. Can Res. 2007;67(1):186\u201393.","journal-title":"Can Res"},{"issue":"3","key":"3024_CR55","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.radonc.2007.05.016","volume":"83","author":"MW Dewhirst","year":"2007","unstructured":"Dewhirst MW, Cao Y, Li CY, Moeller B. Exploring the role of HIF-1 in early angiogenesis and response to radiotherapy. Radiotherapy Oncol. 2007;83(3):249\u201355.","journal-title":"Radiotherapy Oncol"},{"issue":"1","key":"3024_CR56","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/s13046-019-1092-4","volume":"38","author":"C Wei","year":"2019","unstructured":"Wei C, Dong X, Lu H, Tong F, Chen L, Zhang R, et al. LPCAT1 promotes brain metastasis of lung adenocarcinoma by up-regulating PI3K\/AKT\/MYC pathway. J Exp Clin Cancer Res. 2019;38(1):95.","journal-title":"J Exp Clin Cancer Res"},{"key":"3024_CR57","doi-asserted-by":"publisher","unstructured":"Martin E, El-Behi M, Fontaine B, Delarasse C. Analysis of Microglia and Monocyte-derived Macrophages from the Central Nervous System by Flow Cytometry. Journal of visualized experiments : JoVE. 2017(124). https:\/\/doi.org\/10.3791\/55781.","DOI":"10.3791\/55781"},{"key":"3024_CR58","doi-asserted-by":"publisher","unstructured":"Luo Z, Thorvaldson L, Blixt M, Singh K. Determination of Regulatory T Cell Subsets in Murine Thymus, Pancreatic Draining Lymph Node and Spleen Using Flow Cytometry. Journal of visualized experiments : JoVE. 2019(144). https:\/\/doi.org\/10.3791\/58848.","DOI":"10.3791\/58848"},{"issue":"4","key":"3024_CR59","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1667\/RR14374.1","volume":"186","author":"N Yang","year":"2016","unstructured":"Yang N, Gao X, Qu X, Zhang R, Tong F, Cai Q, et al. PIDD Mediates Radiation-Induced Microglia Activation. Radiat Res. 2016;186(4):345\u201359.","journal-title":"Radiat Res"},{"key":"3024_CR60","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.canlet.2017.10.018","volume":"412","author":"RM Liu","year":"2018","unstructured":"Liu RM, Sun DN, Jiao YL, Wang P, Zhang J, Wang M, et al. Macrophage migration inhibitory factor promotes tumor aggressiveness of esophageal squamous cell carcinoma via activation of Akt and inactivation of GSK3\u03b2. Cancer Lett. 2018;412:289\u201396.","journal-title":"Cancer Lett"},{"issue":"48","key":"3024_CR61","doi-asserted-by":"publisher","first-page":"6246","DOI":"10.1038\/onc.2016.160","volume":"35","author":"A Ghoochani","year":"2016","unstructured":"Ghoochani A, Schwarz MA, Yakubov E, Engelhorn T, Doerfler A, Buchfelder M, et al. MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis. Oncogene. 2016;35(48):6246\u201361.","journal-title":"Oncogene"},{"issue":"4","key":"3024_CR62","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1080\/08923973.2022.2055565","volume":"44","author":"X Wu","year":"2022","unstructured":"Wu X, Pu L, Chen W, Zhao Q, Wu G, Li D, et al. LY294002 attenuates inflammatory response in endotoxin-induced uveitis by downregulating JAK3 and inactivating the PI3K\/Akt signaling. Immunopharmacol Immunotoxicol. 2022;44(4):510\u20138.","journal-title":"Immunopharmacol Immunotoxicol"},{"issue":"9","key":"3024_CR63","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1111\/cns.13899","volume":"28","author":"F Yu","year":"2022","unstructured":"Yu F, Wang Y, Stetler AR, Leak RK, Hu X, Chen J. Phagocytic microglia and macrophages in brain injury and repair. CNS Neurosci Ther. 2022;28(9):1279\u201393.","journal-title":"CNS Neurosci Ther"},{"issue":"2","key":"3024_CR64","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.canlet.2008.02.012","volume":"265","author":"M Larsen","year":"2008","unstructured":"Larsen M, Tazzyman S, Lund EL, Junker N, Lewis CE, Kristjansen PE, et al. Hypoxia-induced secretion of macrophage migration-inhibitory factor from MCF-7 breast cancer cells is regulated in a hypoxia-inducible factor-independent manner. Cancer Lett. 2008;265(2):239\u201349.","journal-title":"Cancer Lett"},{"issue":"2","key":"3024_CR65","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1593\/neo.132034","volume":"16","author":"G Zhu","year":"2014","unstructured":"Zhu G, Tang Y, Geng N, Zheng M, Jiang J, Li L, et al. HIF-\u03b1\/MIF and NF-\u03baB\/IL-6 axes contribute to the recruitment of CD11b+Gr-1+ myeloid cells in hypoxic microenvironment of HNSCC. Neoplasia (New York, NY). 2014;16(2):168\u201379.","journal-title":"Neoplasia (New York, NY)"},{"key":"3024_CR66","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.829451","volume":"13","author":"Y Wang","year":"2022","unstructured":"Wang Y, Chen R, Wa Y, Ding S, Yang Y, Liao J, et al. Tumor Immune Microenvironment and Immunotherapy in Brain Metastasis From Non-Small Cell Lung Cancer. Front Immunol. 2022;13: 829451.","journal-title":"Front Immunol"},{"issue":"4","key":"3024_CR67","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1111\/bph.13139","volume":"173","author":"R Orihuela","year":"2016","unstructured":"Orihuela R, McPherson CA, Harry GJ. Microglial M1\/M2 polarization and metabolic states. Br J Pharmacol. 2016;173(4):649\u201365.","journal-title":"Br J Pharmacol"},{"key":"3024_CR68","doi-asserted-by":"publisher","unstructured":"Akkari L, Bowman RL, Tessier J, Klemm F, Handgraaf SM, de Groot M, et al. Dynamic changes in glioma macrophage populations after radiotherapy reveal CSF-1R inhibition as a strategy to overcome resistance. Science translational medicine. 2020;12(552). https:\/\/doi.org\/10.1126\/scitranslmed.aaw7843.","DOI":"10.1126\/scitranslmed.aaw7843"},{"key":"3024_CR69","doi-asserted-by":"publisher","unstructured":"Hajji N, Garcia-Revilla J, Soto MS, Perryman R, Symington J, Quarles CC, et al. Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors. The Journal of clinical investigation. 2022;132(6). https:\/\/doi.org\/10.1172\/JCI142137.","DOI":"10.1172\/JCI142137"},{"issue":"1","key":"3024_CR70","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1002\/path.6018","volume":"259","author":"BL Woolbright","year":"2023","unstructured":"Woolbright BL, Rajendran G, Abbott E, Martin A, Amalraj S, Dennis K, et al. Role of MIF1\/MIF2\/CD74 interactions in bladder cancer. J Pathol. 2023;259(1):46\u201355.","journal-title":"J Pathol"},{"key":"3024_CR71","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2021.110075","volume":"86","author":"I Cotzomi-Ortega","year":"2021","unstructured":"Cotzomi-Ortega I, Nieto-Ya\u00f1ez O, Ju\u00e1rez-Avelar I, Rojas-Sanchez G, Montes-Alvarado JB, Reyes-Leyva J, et al. Autophagy inhibition in breast cancer cells induces ROS-mediated MIF expression and M1 macrophage polarization. Cell Signal. 2021;86: 110075.","journal-title":"Cell Signal"},{"issue":"2","key":"3024_CR72","doi-asserted-by":"publisher","first-page":"638","DOI":"10.2353\/ajpath.2009.080463","volume":"174","author":"M McClelland","year":"2009","unstructured":"McClelland M, Zhao L, Carskadon S, Arenberg D. Expression of CD74, the receptor for macrophage migration inhibitory factor, in non-small cell lung cancer. Am J Pathol. 2009;174(2):638\u201346.","journal-title":"Am J Pathol"},{"issue":"2","key":"3024_CR73","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/s41419-021-03426-z","volume":"12","author":"L Klemke","year":"2021","unstructured":"Klemke L, De Oliveira T, Witt D, Winkler N, Bohnenberger H, Bucala R, et al. Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer. Cell Death Dis. 2021;12(2):155.","journal-title":"Cell Death Dis"},{"issue":"6","key":"3024_CR74","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0197702","volume":"13","author":"KN Balogh","year":"2018","unstructured":"Balogh KN, Templeton DJ, Cross JV. Macrophage Migration Inhibitory Factor protects cancer cells from immunogenic cell death and impairs anti-tumor immune responses. PLoS ONE. 2018;13(6): e0197702.","journal-title":"PLoS ONE"},{"issue":"6","key":"3024_CR75","doi-asserted-by":"publisher","first-page":"2984","DOI":"10.4049\/jimmunol.1201650","volume":"190","author":"K Yaddanapudi","year":"2013","unstructured":"Yaddanapudi K, Putty K, Rendon BE, Lamont GJ, Faughn JD, Satoskar A, et al. Control of tumor-associated macrophage alternative activation by macrophage migration inhibitory factor. J Immunol (Baltimore, Md\u202f: 1950). 2013;190(6):2984\u201393.","journal-title":"J Immunol (Baltimore, Md : 1950)."},{"key":"3024_CR76","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1186\/s12957-016-0797-5","volume":"14","author":"J Zhang","year":"2016","unstructured":"Zhang J, Zhang G, Yang S, Qiao J, Li T, Yang S, et al. Macrophage migration inhibitory factor regulating the expression of VEGF-C through MAPK signal pathways in breast cancer MCF-7 cell. World J Surg Oncol. 2016;14:51.","journal-title":"World J Surg Oncol"},{"issue":"20","key":"3024_CR77","doi-asserted-by":"publisher","first-page":"2676","DOI":"10.1038\/s41388-018-0151-1","volume":"37","author":"AM Abdul-Aziz","year":"2018","unstructured":"Abdul-Aziz AM, Shafat MS, Sun Y, Marlein CR, Piddock RE, Robinson SD, et al. HIF1\u03b1 drives chemokine factor pro-tumoral signaling pathways in acute myeloid leukemia. Oncogene. 2018;37(20):2676\u201386.","journal-title":"Oncogene"},{"key":"3024_CR78","doi-asserted-by":"publisher","unstructured":"Thiele M, Donnelly SC, Mitchell RA. OxMIF: a druggable isoform of macrophage migration inhibitory factor in cancer and inflammatory diseases. Journal for immunotherapy of cancer. 2022;10(9). https:\/\/doi.org\/10.1136\/jitc-2022-005475.","DOI":"10.1136\/jitc-2022-005475"},{"issue":"4","key":"3024_CR79","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1111\/bjh.12565","volume":"163","author":"JL Kaufman","year":"2013","unstructured":"Kaufman JL, Niesvizky R, Stadtmauer EA, Chanan-Khan A, Siegel D, Horne H, et al. Phase I, multicentre, dose-escalation trial of monotherapy with milatuzumab (humanized anti-CD74 monoclonal antibody) in relapsed or refractory multiple myeloma. Br J Haematol. 2013;163(4):478\u201386.","journal-title":"Br J Haematol"},{"issue":"11\u201312","key":"3024_CR80","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.drudis.2012.12.013","volume":"18","author":"L Xu","year":"2013","unstructured":"Xu L, Li Y, Sun H, Zhen X, Qiao C, Tian S, et al. Current developments of macrophage migration inhibitory factor (MIF) inhibitors. Drug Discovery Today. 2013;18(11\u201312):592\u2013600.","journal-title":"Drug Discovery Today"},{"issue":"14","key":"3024_CR81","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.2174\/1381612023394674","volume":"8","author":"M Orita","year":"2002","unstructured":"Orita M, Yamamoto S, Katayama N, Fujita S. Macrophage migration inhibitory factor and the discovery of tautomerase inhibitors. Curr Pharm Des. 2002;8(14):1297\u2013317.","journal-title":"Curr Pharm Des"},{"issue":"3","key":"3024_CR82","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1002\/med.21385","volume":"36","author":"C O'Reilly","year":"2016","unstructured":"O\u2019Reilly C, Doroudian M, Mawhinney L, Donnelly SC. Targeting MIF in cancer: therapeutic strategies, current developments, and future opportunities. Med Res Rev. 2016;36(3):440\u201360.","journal-title":"Med Res Rev"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-024-03024-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-024-03024-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-024-03024-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T10:04:20Z","timestamp":1714385060000},"score":1,"resource":{"primary":{"URL":"https:\/\/jeccr.biomedcentral.com\/articles\/10.1186\/s13046-024-03024-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,29]]},"references-count":82,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["3024"],"URL":"https:\/\/doi.org\/10.1186\/s13046-024-03024-9","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-3520330\/v1","asserted-by":"object"}]},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,29]]},"assertion":[{"value":"5 November 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Institutional Review Board of Huazhong University of Science and Technology. Written informed consent was obtained from all legal guardians of the patients. All animal experiments were conducted in agreement with the Guide for the Care and Use of Laboratory Animals and were approved by the Committee on Animal Handling of Huazhong University of Science and Technology.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All the authors are consent for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"128"}}