{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T06:23:14Z","timestamp":1793946194458,"version":"4.8.0"},"reference-count":48,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sig Transduct Target Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, particularly in the presence of liver metastases. The mechanisms by which metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), influences PDAC progression and metastasis remain poorly understood. This study investigates the role of MASLD in fostering an immunosuppressive microenvironment conducive to PDAC liver metastases and identifies the macrophage migration inhibitory factor (MIF)-CD44 axis as a key mediator of this process. Utilizing data from the UK Biobank (450,754 participants, median follow-up 14.5 years), we observed an overall increased risk of PDAC in the MASLD population (HR: 3.48; 95% CI: 2.69\u20134.50; P\u2009&lt;\u20090.0001). Clinical cohorts confirmed the strong association between MASLD and hepatic metastases (OR: 7.06; 95% CI: 4.62\u201310.78; P\u2009&lt;\u20090.0001). Experimental mouse models demonstrated that MASLD enhances tumor cell stemness, immune evasion, and focal adhesion in metastatic liver tissues. Mechanistically, MASLD-induced MIF secretion promotes CD44-positive PDAC cell migration, stemness, and adhesion. Targeting MIF, either genetically or pharmacologically using the MIF tautomerase inhibitor IPG1576 significantly attenuated liver metastasis in preclinical models. Validation in patient samples revealed elevated hepatic MIF and CD44 expression in MASLD-associated PDAC liver metastases. This study highlights the MIF-CD44 axis as a promising therapeutic target and underscores the importance of tailoring treatments for PDAC patients with concurrent MASLD.<\/jats:p>","DOI":"10.1038\/s41392-025-02562-8","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:15:24Z","timestamp":1768565724000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Metabolic dysfunction-associated steatotic liver disease accelerates pancreatic cancer progression and metastasis via the macrophage migration inhibitory factor-CD44 axis"],"prefix":"10.1038","volume":"11","author":[{"given":"Qian","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-ya","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-ning","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-wu","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shang-long","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-zhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-luo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiu-fa","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-nan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4639-7303","authenticated-orcid":false,"given":"Zhan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-tian","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie-er","family":"Ying","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei-fang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7189-3999","authenticated-orcid":false,"given":"Yan-tao","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-tao","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-xin","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-guang","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun-li","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-hui","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1139-1361","authenticated-orcid":false,"given":"Yuan-yu","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-yang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok K.","family":"Saluja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-gang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-yu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song-yue","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-hua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-tao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9528-0580","authenticated-orcid":false,"given":"He","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"2562_CR1","first-page":"10","volume":"75","author":"RL Siegel","year":"2025","unstructured":"Siegel, R. L., Kratzer, T. B., Giaquinto, A. N., Sung, H. & Jemal, A. Cancer statistics, 2025. CA Cancer J. Clin. 75, 10\u201345 (2025).","journal-title":"CA Cancer J. Clin."},{"key":"2562_CR2","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-022-10130-4","volume":"22","author":"L Miotke","year":"2022","unstructured":"Miotke, L. et al. Treatment outcomes in recurrent versus de novo metastatic pancreatic adenocarcinoma: a real-world study. BMC Cancer 22, 1054 (2022).","journal-title":"BMC Cancer"},{"key":"2562_CR3","doi-asserted-by":"publisher","first-page":"156004","DOI":"10.1016\/j.metabol.2024.156004","volume":"160","author":"M Kalligeros","year":"2024","unstructured":"Kalligeros, M., Henry, L. & Younossi, Z. M. Metabolic dysfunction-associated steatotic liver disease and its link to cancer. Metabolism 160, 156004 (2024).","journal-title":"Metabolism"},{"key":"2562_CR4","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/s00595-019-01866-x","volume":"50","author":"H Okabe","year":"2020","unstructured":"Okabe, H. et al. Postoperative nonalcoholic fatty liver disease is correlated with malnutrition leading to an unpreferable clinical course for pancreatic cancer patients undergoing pancreaticoduodenectomy. Surg. Today 50, 193\u2013199 (2020).","journal-title":"Surg. Today"},{"key":"2562_CR5","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/nrgastro.2013.53","volume":"10","author":"A Brouquet","year":"2013","unstructured":"Brouquet, A. & Nordlinger, B. Metastatic colorectal cancer outcome and fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 10, 266\u2013267 (2013).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"2562_CR6","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1002\/bjs.9057","volume":"100","author":"ZZ Hamady","year":"2013","unstructured":"Hamady, Z. Z. et al. Fatty liver disease as a predictor of local recurrence following resection of colorectal liver metastases. Br. J. Surg. 100, 820\u2013826 (2013).","journal-title":"Br. J. Surg."},{"key":"2562_CR7","first-page":"963","volume":"20","author":"A Ocak Duran","year":"2015","unstructured":"Ocak Duran, A. et al. Hepatic steatosis is associated with higher incidence of liver metastasis in patients with metastatic breast cancer; an observational clinical study. J. Buon. 20, 963\u2013969 (2015).","journal-title":"J. Buon."},{"key":"2562_CR8","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1002\/hep.30693","volume":"70","author":"K Ohashi","year":"2019","unstructured":"Ohashi, K. et al. NOD-like receptor C4 inflammasome regulates the growth of colon cancer liver metastasis in NAFLD. Hepatology 70, 1582\u20131599 (2019).","journal-title":"Hepatology"},{"key":"2562_CR9","doi-asserted-by":"crossref","unstructured":"Sanna, C., Rosso, C., Marietti, M. & Bugianesi, E. Non-alcoholic fatty liver disease and extra-hepatic cancers. Int. J. Mol. Sci. 17, 717 (2016).","DOI":"10.3390\/ijms17050717"},{"key":"2562_CR10","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1016\/j.jhep.2019.08.018","volume":"71","author":"AM Allen","year":"2019","unstructured":"Allen, A. M., Hicks, S. B., Mara, K. C., Larson, J. J. & Therneau, T. M. The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity\u2014a longitudinal cohort study. J. Hepatol. 71, 1229\u20131236 (2019).","journal-title":"J. Hepatol."},{"key":"2562_CR11","doi-asserted-by":"publisher","first-page":"2410","DOI":"10.1002\/hep.31845","volume":"74","author":"TG Simon","year":"2021","unstructured":"Simon, T. G. et al. Cancer risk in patients with biopsy-confirmed nonalcoholic fatty liver disease: a population-based cohort study. Hepatology 74, 2410\u20132423 (2021).","journal-title":"Hepatology"},{"key":"2562_CR12","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1097\/00004836-200304000-00015","volume":"36","author":"HT S\u00f8rensen","year":"2003","unstructured":"S\u00f8rensen, H. T. et al. Risk of cancer in patients hospitalized with fatty liver: a Danish cohort study. J. Clin. Gastroenterol. 36, 356\u2013359 (2003).","journal-title":"J. Clin. Gastroenterol."},{"key":"2562_CR13","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1007\/s11739-017-1774-x","volume":"13","author":"CF Chang","year":"2018","unstructured":"Chang, C. F. et al. Exploring the relationship between nonalcoholic fatty liver disease and pancreatic cancer by computed tomographic survey. Intern. Emerg. Med. 13, 191\u2013197 (2018).","journal-title":"Intern. Emerg. Med."},{"key":"2562_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-14856-w","volume":"12","author":"JH Park","year":"2022","unstructured":"Park, J. H., Hong, J. Y., Han, K., Kang, W. & Park, J. K. Increased risk of pancreatic cancer in individuals with non-alcoholic fatty liver disease. Sci. Rep. 12, 10681 (2022).","journal-title":"Sci. Rep."},{"key":"2562_CR15","doi-asserted-by":"crossref","unstructured":"Soares, K. C. et al. A preclinical murine model of hepatic metastases. J. Vis. Exp. 51677 (2014).","DOI":"10.3791\/51677-v"},{"key":"2562_CR16","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/s41586-024-07715-3","volume":"632","author":"C Borrelli","year":"2024","unstructured":"Borrelli, C. et al. In vivo interaction screening reveals liver-derived constraints to metastasis. Nature 632, 411\u2013418 (2024).","journal-title":"Nature"},{"key":"2562_CR17","doi-asserted-by":"publisher","first-page":"1938","DOI":"10.1016\/j.bbadis.2016.07.014","volume":"1862","author":"M Klobu\u010dar","year":"2016","unstructured":"Klobu\u010dar, M. et al. Basement membrane protein ladinin-1 and the MIF-CD44-\u03b21 integrin signaling axis are implicated in laryngeal cancer metastasis. Biochim. Biophys. Acta. 1862, 1938\u20131954 (2016).","journal-title":"Biochim. Biophys. Acta."},{"key":"2562_CR18","doi-asserted-by":"crossref","unstructured":"Heinrichs, D. et al. Unexpected pro-fibrotic effect of MIF in non-alcoholic steatohepatitis is linked to a shift in NKT cell populations. Cells 10, 252 (2021).","DOI":"10.3390\/cells10020252"},{"key":"2562_CR19","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/j.jhep.2017.06.014","volume":"67","author":"V Marin","year":"2017","unstructured":"Marin, V. et al. Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients. J. Hepatol. 67, 1018\u20131025 (2017).","journal-title":"J. Hepatol."},{"key":"2562_CR20","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1158\/2326-6066.CIR-15-0070-T","volume":"4","author":"K Yaddanapudi","year":"2016","unstructured":"Yaddanapudi, K. et al. MIF is necessary for late-stage melanoma patient MDSC immune suppression and differentiation. Cancer Immunol. Res. 4, 101\u2013112 (2016).","journal-title":"Cancer Immunol. Res."},{"key":"2562_CR21","doi-asserted-by":"crossref","unstructured":"Lewinsky, H. et al. CD84 is a regulator of the immunosuppressive microenvironment in multiple myeloma. JCI Insight 6, e141683 (2021).","DOI":"10.1172\/jci.insight.141683"},{"key":"2562_CR22","doi-asserted-by":"publisher","first-page":"5533","DOI":"10.4049\/jimmunol.1201161","volume":"189","author":"KD Simpson","year":"2012","unstructured":"Simpson, K. D., Templeton, D. J. & Cross, J. V. Macrophage migration inhibitory factor promotes tumor growth and metastasis by inducing myeloid-derived suppressor cells in the tumor microenvironment. J. Immunol. 189, 5533\u20135540 (2012).","journal-title":"J. Immunol."},{"key":"2562_CR23","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/ncb3169","volume":"17","author":"B Costa-Silva","year":"2015","unstructured":"Costa-Silva, B. et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816\u2013826 (2015).","journal-title":"Nat. Cell Biol."},{"key":"2562_CR24","doi-asserted-by":"crossref","unstructured":"Jia, X. et al. The tautomerase activity of tumor exosomal MIF promotes pancreatic cancer progression by modulating MDSC differentiation. Cancer Immunol. Res. 12, 72\u201390 (2023).","DOI":"10.1158\/2326-6066.CIR-23-0205"},{"key":"2562_CR25","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.2337\/db16-1477","volume":"66","author":"DK Andersen","year":"2017","unstructured":"Andersen, D. K. et al. Diabetes, pancreatogenic diabetes, and pancreatic cancer. Diabetes 66, 1103\u20131110 (2017).","journal-title":"Diabetes"},{"key":"2562_CR26","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1016\/j.jcmgh.2021.05.010","volume":"12","author":"S Ganguly","year":"2021","unstructured":"Ganguly, S. et al. Nonalcoholic steatohepatitis and HCC in a hyperphagic mouse accelerated by Western diet. Cell Mol. Gastroenterol. Hepatol. 12, 891\u2013920 (2021).","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"2562_CR27","doi-asserted-by":"publisher","first-page":"G483","DOI":"10.1152\/ajpgi.00079.2013","volume":"305","author":"JR Clapper","year":"2013","unstructured":"Clapper, J. R. et al. Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G483\u2013G495 (2013).","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"2562_CR28","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1093\/toxsci\/kfx253","volume":"161","author":"H Li","year":"2018","unstructured":"Li, H., Toth, E. & Cherrington, N. J. Asking the right questions with animal models: methionine- and choline-deficient model in predicting adverse drug reactions in human NASH. Toxicol. Sci. 161, 23\u201333 (2018).","journal-title":"Toxicol. Sci."},{"key":"2562_CR29","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1111\/iep.12008","volume":"94","author":"M Matsumoto","year":"2013","unstructured":"Matsumoto, M. et al. An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis. Int. J. Exp. Pathol. 94, 93\u2013103 (2013).","journal-title":"Int. J. Exp. Pathol."},{"key":"2562_CR30","doi-asserted-by":"publisher","first-page":"2628","DOI":"10.1016\/j.apsb.2023.03.008","volume":"13","author":"Q Yu","year":"2023","unstructured":"Yu, Q. et al. Hepatic COX1 loss leads to impaired autophagic flux and exacerbates nonalcoholic steatohepatitis. Acta Pharm. Sin. B. 13, 2628\u20132644 (2023).","journal-title":"Acta Pharm. Sin. B."},{"key":"2562_CR31","doi-asserted-by":"publisher","first-page":"216859","DOI":"10.1016\/j.canlet.2024.216859","volume":"591","author":"Q Qin","year":"2024","unstructured":"Qin, Q., Yu, R., Eriksson, J. E., Tsai, H. I. & Zhu, H. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma therapy: challenges and opportunities. Cancer Lett. 591, 216859 (2024).","journal-title":"Cancer Lett."},{"key":"2562_CR32","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/j.ccell.2024.03.009","volume":"42","author":"M Liu","year":"2024","unstructured":"Liu, M. et al. The crosstalk between macrophages and cancer cells potentiates pancreatic cancer cachexia. Cancer Cell 42, 885\u2013903.e884 (2024).","journal-title":"Cancer Cell"},{"key":"2562_CR33","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.216894","volume":"591","author":"M El-Tanani","year":"2024","unstructured":"El-Tanani, M. et al. Unraveling the tumor microenvironment: Insights into cancer metastasis and therapeutic strategies. Cancer Lett. 591, 216894 (2024).","journal-title":"Cancer Lett."},{"key":"2562_CR34","doi-asserted-by":"publisher","first-page":"2094","DOI":"10.1200\/JCO.1995.13.8.2094","volume":"13","author":"JL Abbruzzese","year":"1995","unstructured":"Abbruzzese, J. L., Abbruzzese, M. C., Lenzi, R., Hess, K. R. & Raber, M. N. Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J. Clin. Oncol. 13, 2094\u20132103 (1995).","journal-title":"J. Clin. Oncol."},{"key":"2562_CR35","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.tem.2022.02.002","volume":"33","author":"X Weng","year":"2022","unstructured":"Weng, X., Maxwell-Warburton, S., Hasib, A., Ma, L. & Kang, L. The membrane receptor CD44: novel insights into metabolism. Trends Endocrinol. Metab. 33, 318\u2013332 (2022).","journal-title":"Trends Endocrinol. Metab."},{"key":"2562_CR36","doi-asserted-by":"publisher","first-page":"4850","DOI":"10.1172\/JCI59261","volume":"121","author":"Y Malato","year":"2011","unstructured":"Malato, Y. et al. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J. Clin. Invest 121, 4850\u20134860 (2011).","journal-title":"J. Clin. Invest"},{"key":"2562_CR37","doi-asserted-by":"publisher","first-page":"2419","DOI":"10.1158\/0008-5472.CAN-15-1691","volume":"76","author":"Y Yan","year":"2016","unstructured":"Yan, Y. et al. KLF4-mediated suppression of CD44 signaling negatively impacts pancreatic cancer stemness and metastasis. Cancer Res. 76, 2419\u20132431 (2016).","journal-title":"Cancer Res."},{"key":"2562_CR38","doi-asserted-by":"publisher","DOI":"10.1002\/mog2.62","volume":"2","author":"J Talukdar","year":"2023","unstructured":"Talukdar, J. et al. Cancer stem cells: Signaling pathways and therapeutic targeting. MedComm \u2013 Oncol. 2, e62 (2023).","journal-title":"MedComm \u2013 Oncol."},{"key":"2562_CR39","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/j.cell.2019.03.010","volume":"177","author":"NK Lytle","year":"2019","unstructured":"Lytle, N. K. et al. A multiscale map of the stem cell state in pancreatic adenocarcinoma. Cell 177, 572\u2013586.e522 (2019).","journal-title":"Cell"},{"key":"2562_CR40","doi-asserted-by":"publisher","first-page":"1898","DOI":"10.1053\/j.gastro.2020.07.053","volume":"159","author":"S Karmakar","year":"2020","unstructured":"Karmakar, S. et al. RNA polymerase II-associated factor 1 regulates stem cell features of pancreatic cancer cells, independently of the PAF1 complex, via interactions with PHF5A and DDX3. Gastroenterology 159, 1898\u20131915.e1896 (2020).","journal-title":"Gastroenterology"},{"key":"2562_CR41","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1023\/A:1026519016213","volume":"18","author":"RC Casey","year":"2000","unstructured":"Casey, R. C. & Skubitz, A. P. CD44 and beta1 integrins mediate ovarian carcinoma cell migration toward extracellular matrix proteins. Clin. Exp. Metastasis 18, 67\u201375 (2000).","journal-title":"Clin. Exp. Metastasis"},{"key":"2562_CR42","doi-asserted-by":"crossref","unstructured":"Chu, Y. H. et al. Targeting chondroitin sulfate reduces invasiveness of glioma cells by suppressing CD44 and integrin \u03b21 expression. Cells 10, 3594 (2021).","DOI":"10.3390\/cells10123594"},{"key":"2562_CR43","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1158\/2326-6066.CIR-23-0205","volume":"12","author":"X Jia","year":"2024","unstructured":"Jia, X. et al. The tautomerase activity of tumor exosomal Mif promotes pancreatic cancer progression by modulating MDSC differentiation. Cancer Immunol. Res. 12, 72\u201390 (2024).","journal-title":"Cancer Immunol. Res."},{"key":"2562_CR44","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1016\/j.cmet.2023.04.013","volume":"35","author":"Z Wang","year":"2023","unstructured":"Wang, Z. et al. Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment. Cell Metab. 35, 1209\u20131226.e1213 (2023).","journal-title":"Cell Metab."},{"key":"2562_CR45","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/nm1567","volume":"13","author":"J Bernhagen","year":"2007","unstructured":"Bernhagen, J. et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat. Med. 13, 587\u2013596 (2007).","journal-title":"Nat. Med."},{"key":"2562_CR46","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/nri1200","volume":"3","author":"T Calandra","year":"2003","unstructured":"Calandra, T. & Roger, T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat. Rev. Immunol. 3, 791\u2013800 (2003).","journal-title":"Nat. Rev. Immunol."},{"key":"2562_CR47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1555036","volume":"16","author":"R Gong","year":"2025","unstructured":"Gong, R. et al. Targeting myeloid cells in pancreatic ductal adenocarcinoma: from primary tumors to liver metastasis. Front Immunol. 16, 1555036 (2025).","journal-title":"Front Immunol."},{"key":"2562_CR48","doi-asserted-by":"publisher","first-page":"e89","DOI":"10.1002\/mog2.89","volume":"3","author":"Y Bai","year":"2024","unstructured":"Bai, Y., Xu, H., Guo, M., Xia, L. & Deng, S. Extensive infiltration of CD8+ T cells and M1 macrophages is beneficial for multiple cancer patients undergoing chemotherapy. MedComm\u2014Oncol. 3, e89 (2024).","journal-title":"MedComm\u2014Oncol."}],"container-title":["Signal Transduction and Targeted Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02562-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02562-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02562-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:03:05Z","timestamp":1768568585000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41392-025-02562-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,16]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2562"],"URL":"https:\/\/doi.org\/10.1038\/s41392-025-02562-8","relation":{},"ISSN":["2059-3635"],"issn-type":[{"value":"2059-3635","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,16]]},"assertion":[{"value":"3 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 December 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 January 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Y. Li is affiliated with Immunophage Biotech Co., Ltd, while M.G. Mo works at Cobio Biotechnology Co., Ltd. Both researchers supply the drug IPG1576 in this research work. The other authors declare no conflicts of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This retrospective clinical study received approval from the National Health Commission Clinical Research Ethics Committee (Approval No. QYFYEC2024-50). The use of human liver tissues was additionally approved by the Affiliated Hospital of Qingdao University Clinical Research Ethics Committee (Approval No. QYFYWZLL28018). All animal studies have been approved by the Laboratory Animal Ethics Committee of the Affiliated Hospital of Qingdao University (Approval No. AHQU-MAL20231113).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"32"}}