{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T23:16:26Z","timestamp":1793661386443,"version":"4.5.1"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/100019397","name":"Actuate Therapeutics","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019397","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2026,5]]},"DOI":"10.1038\/s41591-026-04327-4","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T09:02:48Z","timestamp":1776157368000},"page":"1794-1804","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma: a randomized controlled phase 2 trial"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2979-9894","authenticated-orcid":false,"given":"Devalingam","family":"Mahalingam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0066-2672","authenticated-orcid":false,"given":"Rachna T.","family":"Shroff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5468-1126","authenticated-orcid":false,"given":"Benedito A.","family":"Carneiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Coveler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3806-3691","authenticated-orcid":false,"given":"Andres","family":"Cervantes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1892-1548","authenticated-orcid":false,"given":"Vaibhav","family":"Sahai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Ploquin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Hiret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelle K.","family":"LoConte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivor J.","family":"Percent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles D.","family":"Lopez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Pernot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Kavan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Mulcahy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5762-367X","authenticated-orcid":false,"given":"Ryan","family":"Carr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6919-0231","authenticated-orcid":false,"given":"Francis J.","family":"Giles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Seifarth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey","family":"Ugolkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Weiskittel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil","family":"Fine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Jaros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Mazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7721-1699","authenticated-orcid":false,"given":"Tanios S.","family":"Bekaii-Saab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"4327_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":"4327_CR2","doi-asserted-by":"crossref","first-page":"3634","DOI":"10.3390\/cancers15143634","volume":"15","author":"O Partyka","year":"2023","unstructured":"Partyka, O. et al. Overview of pancreatic cancer epidemiology in Europe and recommendations for screening in high-risk populations. Cancers 15, 3634 (2023).","journal-title":"Cancers"},{"key":"4327_CR3","unstructured":"Estimates of Cancer Incidence and Mortality in 2022, for All Countries (European Cancer Information System, accessed 9 October 2025); https:\/\/ecis.jrc.ec.europa.eu\/explorer.php"},{"key":"4327_CR4","unstructured":"Pancreatic Adenocarcinoma (Version 2.2025), Updated February 3 (National Comprehensive Cancer Network, 2025)."},{"key":"4327_CR5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14740\/wjon1166","volume":"10","author":"P Rawla","year":"2019","unstructured":"Rawla, P., Sunkara, T. & Gaduputi, V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J. Oncol. 10, 10\u201327 (2019).","journal-title":"World J. Oncol."},{"key":"4327_CR6","doi-asserted-by":"crossref","DOI":"10.1016\/j.ctrv.2021.102180","volume":"96","author":"S De Dosso","year":"2021","unstructured":"De Dosso, S. et al. Treatment landscape of metastatic pancreatic cancer. Cancer Treat. Rev. 96, 102180 (2021).","journal-title":"Cancer Treat. Rev."},{"key":"4327_CR7","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.annonc.2023.08.009","volume":"34","author":"T Conroy","year":"2023","unstructured":"Conroy, T. et al. Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 34, 987\u20131002 (2023).","journal-title":"Ann. Oncol."},{"key":"4327_CR8","doi-asserted-by":"crossref","first-page":"e2350756","DOI":"10.1001\/jamanetworkopen.2023.50756","volume":"7","author":"F Nichetti","year":"2024","unstructured":"Nichetti, F. et al. NALIRIFOX, FOLFIRINOX, and gemcitabine with nab-paclitaxel as first-line chemotherapy for metastatic pancreatic cancer: a systematic review and meta-analysis. JAMA Netw. Open 7, e2350756 (2024).","journal-title":"JAMA Netw. Open"},{"key":"4327_CR9","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1056\/NEJMoa1011923","volume":"364","author":"T Conroy","year":"2011","unstructured":"Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817\u20131825 (2011).","journal-title":"N. Engl. J. Med."},{"key":"4327_CR10","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1016\/S0140-6736(23)01366-1","volume":"402","author":"ZA Wainberg","year":"2023","unstructured":"Wainberg, Z. A. et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet 402, 1272\u20131281 (2023).","journal-title":"Lancet"},{"key":"4327_CR11","doi-asserted-by":"crossref","first-page":"e2500197","DOI":"10.1200\/PO-25-00197","volume":"9","author":"S Wenric","year":"2025","unstructured":"Wenric, S. et al. Real-world validation of the purity independent subtyping of tumors classifier for informing therapy selection in pancreatic ductal adenocarcinoma. JCO Precis. Oncol. 9, e2500197 (2025).","journal-title":"JCO Precis. Oncol."},{"key":"4327_CR12","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1080\/14796694.2024.2435253","volume":"21","author":"P Cockrum","year":"2025","unstructured":"Cockrum, P., Dennen, S., Brown, A., Briggs, J. & Paluri, R. Real-world clinical outcomes and economic burden of metastatic pancreatic ductal adenocarcinoma: a systematic review. Future Oncol. 21, 241\u2013260 (2025).","journal-title":"Future Oncol."},{"key":"4327_CR13","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1056\/NEJMoa1304369","volume":"369","author":"DD Von Hoff","year":"2013","unstructured":"Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691\u20131703 (2013).","journal-title":"N. Engl. J. Med."},{"key":"4327_CR14","volume":"42","author":"JJ Knox","year":"2024","unstructured":"Knox, J. J. et al. Early results of the PASS-01 trial: pancreatic adenocarcinoma signature stratification for treatment-01. J. Clin. Oncol. 42, LBA4004 (2024).","journal-title":"J. Clin. Oncol."},{"key":"4327_CR15","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1200\/JCO.21.02616","volume":"40","author":"NA Ullman","year":"2022","unstructured":"Ullman, N. A., Burchard, P. R., Dunne, R. F. & Linehan, D. C. Immunologic strategies in pancreatic cancer: making cold tumors hot. J. Clin. Oncol. 40, 2789\u20132805 (2022).","journal-title":"J. Clin. Oncol."},{"key":"4327_CR16","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1056\/NEJMoa1200694","volume":"366","author":"JR Brahmer","year":"2012","unstructured":"Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455\u20132465 (2012).","journal-title":"N. Engl. J. Med."},{"key":"4327_CR17","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1097\/CJI.0b013e3181eec14c","volume":"33","author":"RE Royal","year":"2010","unstructured":"Royal, R. E. et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828\u2013833 (2010).","journal-title":"J. Immunother."},{"key":"4327_CR18","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1001\/jamaoncol.2019.1588","volume":"5","author":"EM O\u2019Reilly","year":"2019","unstructured":"O\u2019Reilly, E. M. et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 5, 1431\u20131438 (2019).","journal-title":"JAMA Oncol."},{"key":"4327_CR19","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-022-32591-8","volume":"13","author":"DJ Renouf","year":"2022","unstructured":"Renouf, D. J. et al. The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma. Nat. Commun. 13, 5020 (2022).","journal-title":"Nat. Commun."},{"key":"4327_CR20","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1158\/0008-5472.CAN-04-3642","volume":"65","author":"AV Ougolkov","year":"2005","unstructured":"Ougolkov, A. V., Fernandez-Zapico, M. E., Savoy, D. N., Urrutia, R. A. & Billadeau, D. D. Glycogen synthase kinase-3\u03b2 participates in nuclear factor \u03baB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res. 65, 2076\u20132081 (2005).","journal-title":"Cancer Res."},{"key":"4327_CR21","doi-asserted-by":"crossref","first-page":"6452","DOI":"10.1158\/1078-0432.CCR-19-0799","volume":"25","author":"L Ding","year":"2019","unstructured":"Ding, L. et al. Glycogen synthase kinase-3 inhibition sensitizes pancreatic cancer cells to chemotherapy by abrogating the TopBP1\/ATR-mediated DNA damage response. Clin. Cancer Res. 25, 6452\u20136462 (2019).","journal-title":"Clin. Cancer Res."},{"key":"4327_CR22","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-019-55176-w","volume":"9","author":"A Jeffers","year":"2019","unstructured":"Jeffers, A. et al. Glycogen synthase kinase-3\u03b2 inhibition with 9-ING-41 attenuates the progression of pulmonary fibrosis. Sci. Rep. 9, 18925 (2019).","journal-title":"Sci. Rep."},{"key":"4327_CR23","doi-asserted-by":"crossref","first-page":"610","DOI":"10.3390\/biology10070610","volume":"10","author":"R Park","year":"2021","unstructured":"Park, R., Coveler, A. L., Cavalcante, L. & Saeed, A. GSK-3\u03b2 in pancreatic cancer: spotlight on 9-ING-41, its therapeutic potential and immune modulatory properties. Biology 10, 610 (2021).","journal-title":"Biology"},{"key":"4327_CR24","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1158\/1078-0432.CCR-15-2240","volume":"23","author":"A Walz","year":"2017","unstructured":"Walz, A. et al. Molecular pathways: revisiting glycogen synthase kinase-3\u03b2 as a target for the treatment of cancer. Clin. Cancer Res. 23, 1891\u20131897 (2017).","journal-title":"Clin. Cancer Res."},{"key":"4327_CR25","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1021\/jm801317h","volume":"52","author":"IN Gaisina","year":"2009","unstructured":"Gaisina, I. N. et al. From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase 3beta inhibitors that suppress proliferation and survival of pancreatic cancer cells. J. Med. Chem. 52, 1853\u20131863 (2009).","journal-title":"J. Med. Chem."},{"key":"4327_CR26","volume":"11","author":"D Choi","year":"2024","unstructured":"Choi, D. et al. Microfluidic organoid cultures derived from pancreatic cancer biopsies for personalized testing of chemotherapy and immunotherapy. Adv. Sci. 11, e2303088 (2024).","journal-title":"Adv. Sci."},{"key":"4327_CR27","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1158\/1078-0432.CCR-23-1916","volume":"30","author":"BA Carneiro","year":"2024","unstructured":"Carneiro, B. A. et al. Phase I study of elraglusib (9-ING-41), a glycogen synthase kinase-3\u03b2 inhibitor, as monotherapy or combined with chemotherapy in patients with advanced malignancies. Clin. Cancer Res. 30, 522\u2013531 (2024).","journal-title":"Clin. Cancer Res."},{"key":"4327_CR28","doi-asserted-by":"crossref","DOI":"10.1016\/j.esmoop.2025.105122","volume":"10","author":"D Mahalingam","year":"2025","unstructured":"Mahalingam, D. et al. Phase II study of elraglusib (9-ING-41), a GSK-3\u03b2 inhibitor, in combination with gemcitabine plus nab-paclitaxel in previously untreated metastatic pancreatic cancer. ESMO Open 10, 105122 (2025).","journal-title":"ESMO Open"},{"key":"4327_CR29","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2025.43.16_suppl.4185","volume":"43","author":"T Weiskittel","year":"2025","unstructured":"Weiskittel, T. et al. Machine learning and statistical prediction of overall survival (OS) from pre-dose plasma biomarkers in a randomized phase 2 trial (1801 Part 3B) of the GSK-3 inhibitor elraglusib in metastatic pancreatic ductal adenocarcinoma (mPDAC): Application toward patient enrichment. J. Clin. Oncol. 43, 4185 (2025).","journal-title":"J. Clin. Oncol."},{"key":"4327_CR30","doi-asserted-by":"crossref","DOI":"10.1186\/s13045-022-01352-x","volume":"15","author":"G Shaw","year":"2022","unstructured":"Shaw, G., Cavalcante, L., Giles, F. J. & Taylor, A. Elraglusib (9-ING-41), a selective small-molecule inhibitor of glycogen synthase kinase-3 beta, reduces expression of immune checkpoint molecules PD-1, TIGIT and LAG-3 and enhances CD8+ T cell cytolytic killing of melanoma cells. J. Hematol. Oncol. 15, 134 (2022).","journal-title":"J. Hematol. Oncol."},{"key":"4327_CR31","first-page":"336","volume":"3","author":"ME Issa","year":"2021","unstructured":"Issa, M. E. & Rudd, C. E. Glycogen synthase kinase-3 (GSK-3) regulation of inhibitory coreceptor expression in T-cell immunity. J. Cell. Immunol. 3, 336\u2013342 (2021).","journal-title":"J. Cell. Immunol."},{"key":"4327_CR32","doi-asserted-by":"crossref","first-page":"5664","DOI":"10.1158\/0008-5472.CAN-17-0799","volume":"77","author":"F Cichocki","year":"2017","unstructured":"Cichocki, F. et al. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Cancer Res. 77, 5664\u20135675 (2017).","journal-title":"Cancer Res."},{"key":"4327_CR33","doi-asserted-by":"crossref","first-page":"e002114","DOI":"10.1136\/jitc-2020-002114","volume":"9","author":"Z-X Wang","year":"2021","unstructured":"Wang, Z.-X. et al. Exploration of modified progression-free survival as a novel surrogate endpoint for overall survival in immuno-oncology trials. J. Immunother. Cancer 9, e002114 (2021).","journal-title":"J. Immunother. Cancer"},{"key":"4327_CR34","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1111\/bcp.14316","volume":"86","author":"Y Abdou","year":"2020","unstructured":"Abdou, Y. et al. Mechanism-based treatment of cancer with immune checkpoint inhibitor therapies. Br. J. Clin. Pharmacol. 86, 1690\u20131702 (2020).","journal-title":"Br. J. Clin. Pharmacol."},{"key":"4327_CR35","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1158\/1078-0432.CCR-17-1902","volume":"24","author":"SL Mushti","year":"2018","unstructured":"Mushti, S. L., Mulkey, F. & Sridhara, R. Evaluation of overall response rate and progression-free survival as potential surrogate endpoints for overall survival in immunotherapy trials. Clin. Cancer Res. 24, 2268\u20132275 (2018).","journal-title":"Clin. Cancer Res."},{"key":"4327_CR36","first-page":"1","volume":"106","author":"RC Nie","year":"2019","unstructured":"Nie, R. C. et al. Evaluation of objective response, disease control and progression-free survival as surrogate end-points for overall survival in anti-programmed death-1 and anti-programmed death ligand 1 trials. Eur. J. Cancer 106, 1\u201311 (2019).","journal-title":"Eur. J. Cancer"},{"key":"4327_CR37","doi-asserted-by":"crossref","first-page":"2706","DOI":"10.1200\/JCO.23.00225","volume":"41","author":"M Merino","year":"2023","unstructured":"Merino, M. et al. Irreconcilable differences: the divorce between response rates, progression-free survival, and overall survival. J. Clin. Oncol. 41, 2706\u20132712 (2023).","journal-title":"J. Clin. Oncol."},{"key":"4327_CR38","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nm1339","volume":"12","author":"JJ Trowbridge","year":"2006","unstructured":"Trowbridge, J. J., Xenocostas, A., Moon, R. T. & Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat. Med. 12, 89\u201398 (2006).","journal-title":"Nat. Med."},{"key":"4327_CR39","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/sj.bmt.1705872","volume":"41","author":"RE Kast","year":"2008","unstructured":"Kast, R. E. How lithium treatment generates neutrophilia by enhancing phosphorylation of GSK-3, increasing HIF-1 levels and how this path is important during engraftment. Bone Marrow Transplant. 41, 23\u201326 (2008).","journal-title":"Bone Marrow Transplant."},{"key":"4327_CR40","doi-asserted-by":"publisher","unstructured":"Pang, W. M., Lim, W. M., Ngai, Z. N. & Koh, R. Y. Molecular mechanisms of immune resistance in pancreatic cancer: an update. Curr. Pharm. Biotechnol. (in the press); https:\/\/doi.org\/10.2174\/0113892010365485250330110031","DOI":"10.2174\/0113892010365485250330110031"},{"key":"4327_CR41","doi-asserted-by":"crossref","DOI":"10.1186\/s13045-024-01561-6","volume":"17","author":"P Farhangnia","year":"2024","unstructured":"Farhangnia, P., Khorramdelazad, H., Nickho, H. & Delbandi, A.-A. Current and future immunotherapeutic approaches in pancreatic cancer treatment. J. Hematol. Oncol. 17, 40 (2024).","journal-title":"J. Hematol. Oncol."},{"key":"4327_CR42","doi-asserted-by":"crossref","first-page":"3108","DOI":"10.1158\/1078-0432.CCR-14-2261","volume":"21","author":"D Di Mitri","year":"2015","unstructured":"Di Mitri, D., Toso, A. & Alimonti, A. Molecular pathways: targeting tumor-infiltrating myeloid-derived suppressor cells for cancer therapy. Clin. Cancer Res. 21, 3108\u20133112 (2015).","journal-title":"Clin. Cancer Res."},{"key":"4327_CR43","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.jcmgh.2021.07.006","volume":"12","author":"SB Kemp","year":"2021","unstructured":"Kemp, S. B., Pasca di Magliano, M. & Crawford, H. C. Myeloid cell mediated immune suppression in pancreatic cancer. Cell. Mol. Gastroenterol. Hepatol. 12, 1531\u20131542 (2021).","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"4327_CR44","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2024.112949","volume":"142","author":"S Rajkumari","year":"2024","unstructured":"Rajkumari, S., Singh, J., Agrawal, U. & Agrawal, S. Myeloid-derived suppressor cells in cancer: current knowledge and future perspectives. Int. Immunopharmacol. 142, 112949 (2024).","journal-title":"Int. Immunopharmacol."},{"key":"4327_CR45","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/s41577-020-00490-y","volume":"21","author":"F Veglia","year":"2021","unstructured":"Veglia, F., Sanseviero, E. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat. Rev. Immunol. 21, 485\u2013498 (2021).","journal-title":"Nat. Rev. Immunol."},{"key":"4327_CR46","doi-asserted-by":"crossref","first-page":"992","DOI":"10.20892\/j.issn.2095-3941.2020.0806","volume":"18","author":"H Tang","year":"2021","unstructured":"Tang, H., Li, H. & Sun, Z. Targeting myeloid-derived suppressor cells for cancer therapy. Cancer Biol. Med. 18, 992\u20131009 (2021).","journal-title":"Cancer Biol. Med."},{"key":"4327_CR47","volume":"25","author":"Y Lv","year":"2025","unstructured":"Lv, Y. et al. CXCL2: a key player in the tumor microenvironment and inflammatory diseases. Cancer Cell Int. 25, 133 (2025).","journal-title":"Cancer Cell Int."},{"key":"4327_CR48","volume":"8","author":"Y Ju","year":"2024","unstructured":"Ju, Y. et al. Barriers and opportunities in pancreatic cancer immunotherapy. NPJ Precis. Oncol. 8, 199 (2024).","journal-title":"NPJ Precis. Oncol."},{"key":"4327_CR49","doi-asserted-by":"crossref","first-page":"6419","DOI":"10.3390\/jcm13216419","volume":"13","author":"RC Chick","year":"2024","unstructured":"Chick, R. C. & Pawlik, T. M. Updates in immunotherapy for pancreatic cancer. J. Clin. Med. 13, 6419 (2024).","journal-title":"J. Clin. Med."},{"key":"4327_CR50","doi-asserted-by":"crossref","DOI":"10.1158\/1538-7445.AM2024-5438","volume":"84","author":"P Pathak","year":"2024","unstructured":"Pathak, P., Lin, E., Phillips, I., Ting, D. & Weekes, C. Abstract C073: FOLFIRINOX with glycogen synthase kinase-3 beta (GSK-3\u03b2) inhibitor elraglusib and transforming growth factor-\u03b2 (TGF\u03b2) inhibitor losartan in untreated metastatic pancreatic ductal adenocarcinoma (PDAC): interim analysis of safety cohort. Cancer Res. 84, C073 (2024).","journal-title":"Cancer Res."},{"key":"4327_CR51","doi-asserted-by":"crossref","first-page":"88376","DOI":"10.18632\/oncotarget.19088","volume":"8","author":"D-T Chen","year":"2017","unstructured":"Chen, D.-T. et al. A Bayesian pick-the-winner design in a randomized phase II clinical trial. Oncotarget 8, 88376\u201388385 (2017).","journal-title":"Oncotarget"},{"key":"4327_CR52","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","volume":"45","author":"EA Eisenhauer","year":"2009","unstructured":"Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228\u2013247 (2009).","journal-title":"Eur. J. Cancer"},{"key":"4327_CR53","unstructured":"CTCAE and Adverse Event Reporting. National Cancer Institute https:\/\/dctd.cancer.gov\/research\/ctep-trials\/for-sites\/adverse-events (2025)."},{"key":"4327_CR54","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1177\/17407745231160074","volume":"20","author":"BC Kahan","year":"2023","unstructured":"Kahan, B. C., White, I. R., Edwards, M. & Harhay, M. O. Using modified intention-to-treat as a principal stratum estimator for failure to initiate treatment. Clin. Trials 20, 269\u2013275 (2023).","journal-title":"Clin. Trials"},{"key":"4327_CR55","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1080\/10543406.2014.971164","volume":"25","author":"M Chang","year":"2015","unstructured":"Chang, M. & Wang, J. The add-arm design for unimodal response curve with unknown mode. J. Biopharm. Stat. 25, 1039\u20131064 (2015).","journal-title":"J. Biopharm. Stat."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04327-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04327-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04327-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T14:03:52Z","timestamp":1779285832000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-026-04327-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":55,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["4327"],"URL":"https:\/\/doi.org\/10.1038\/s41591-026-04327-4","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]},"assertion":[{"value":"15 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"D.M. declares research funding from Amgen, Merck, Oncolytics and Rafael; scientific advisory board work for Actuate Therapeutics and Qurient; an advisory\/speaker bureau for Amgen, Bristol Myers Squibb, Eisai and Exelixis; and institutional research funding from Acepodia, Actuate Therapeutics, ADC Therapeutics, Amgen, AVEO, Bayer, Blueprint Medicines, Bristol Myers Squibb, BioNTech, Dialectic Therapeutics, Epizyme, Fujifilm, ImmuneSensor, Immune-Onc Therapeutics, Leap Therapeutics, Lycera Corp, Merck, Millennium, MiNA Alpha, NGM Biopharmaceuticals, Novartis, Oncolytics, Orano Med, Puma, Qurient, Rafael, Repare Therapeutics, Triumvira Immunologics, Vigeo Therapeutics and Warewolf Therapeutics. R.T.S. declares institutional research funding from Lisata, Merck, Exelixis, Bristol Myers Squibb, Immuno Vaccine, Compass, Actuate, Faeth and Seagen; consultation for AstraZeneca, Boston Scientific, Genentech, Elevar, ICON Clinical Research and Foundation Medicine; and participation in advisory boards for Exelixis, Merck, AstraZeneca, Boehringer Ingelheim and Zymeworks. B.A.C. declares institutional research support from AstraZeneca, Abbvie, Actuate Therapeutics, Astellas, Agenus, Bayer, Dragonfly Therapeutics, Mink Therapeutics, Pfizer, Pyxis Oncology, Repare Therapeutics and Regeneron; and participation in advisory boards for Seattle Genetics and Eisai. A.L.C. declares consultation or participation in advisory boards for Halozyme, Seattle Genetics, Merrimack and Abbvie; institutional research funding from XBiotech, Newlink Genetics, Taiho Pharmaceutical, Immunomedics, Onconova Therapeutics, Lilly, Gilead Sciences, Genentech, Seattle Genetics, AbGenomics International, Halozyme, Novocure, Amgen, Actuate Therapeutics, Surface Oncology, Nucana, Nextrast and AstraZeneca; and travel support from Halozyme, Abbvie and Nucana. A.C. declares institutional research funding from Genentech, Merck Serono, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Natera and Actuate Therapeutics; and participation in advisory board or receipt of speaker fees from AbbVie, Amgen, Merck Serono, GlaxoSmithKline and Roche. V.S. declares institutional research funding from Actuate Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Esanik, Exelixis, Fibrogen, Ipsen, MedImmune, the National Cancer Institute, PanCAN, Cornerstone (previously Rafael), Relay, Repare, Servier, Syros and Transthera; consulting fees from Amplity (previously Lynx Group), AstraZeneca, Autem, Delcath Systems, Histosonics, Ipsen, Incyte, Rafael (previously Cornertsone), Servier and Taiho; receipt of equipment and supplies from Beigene and Cornerstone (previously Rafael); and travel support from ASCO, the Cholangiocarcinoma Foundation, Histosonics, Lynx Group\/Amplity and the National Comprehensive Cancer Network. N.K.L. declares institutional research funding from Exact Sciences. C.D.L. declares institutional research funding from Servier, AstraZeneca, Genentech\/Roche and Taiho. F.J.G. declares stock ownership in Actuate Therapeutics. C.S. is an employee and equity holder in Actuate Therapeutics. A.U. is an employee and equity holder in Actuate Therapeutics. T.W., G.F. and M.J. declare consulting fees from Actuate Therapeutics. A.P.M. is an employee and equity holder in Actuate Therapeutics. T.S.B.-S. declares institutional research funding from Actuate Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Elicio, Esanik, Exelixis, Fibrogen, Jazz, Ipsen, the National Cancer Institute, PanCAN, Cornerstone (previously Rafael), Relay, Repare, RevMed, Servier and Transthera; consulting fees from AstraZeneca, Autem, Amplity (previously Lynx Group), Delcath, Elevar, HistoSonics, Incyte, Ipsen, Jazz, RevMed, Servier, Tallac and TransThera; provision of equipment\/supplies from Cornerstone (previously Rafael); travel and lodging costs from ASCO, the Japanese Society of Clinical Oncology, the BinayTara Foundation, the Cholangiocarcinoma Foundation, HistoSonics, Lynx Group\/Amplity, the National Comprehensive Cancer Network and the Chinese Association of Pancreatology. Y.J., A.P., S.H., I.J.P., S.P., P.K., M.M. and R.C. declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}