{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:30:38Z","timestamp":1784543438232,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T00:00:00Z","timestamp":1777680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"HuniLife Biotechnology Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Stromal remodeling in the tumor microenvironment contributes to multiple myeloma (MM) progression and drug resistance, but the extracellular mediators that drive these changes remain incompletely defined. Extracellular enolase-1 (ENO1), including membrane-associated and secreted forms, has been implicated in tumor progression; however, its role in cancer-associated fibroblast (CAF)-associated stromal reprogramming in MM is unclear. Methods: The effects of extracellular ENO1 on stromal activation and tumor-supportive functions were examined in MM using MM\u2013bone marrow stromal cell (BMSC) co-cultures, lactate production and viability assays, immunoblotting, cytokine analyses, and a subcutaneous xenograft model of bortezomib (BTZ)-resistant MM in male 6\u20137-week-old NOD.Cg-Prkdcscid Il2rgtm1Vst\/Vst (NPG) mice. HuL001, an anti-ENO1 monoclonal antibody, was used to evaluate the therapeutic relevance of extracellular ENO1 targeting. Results: Extracellular ENO1 promoted fibroblast activation protein expression through plasmin-mediated transforming growth factor-\u03b2 (TGF-\u03b2) activation and induced a CAF-associated stromal phenotype marked by enhanced glycolytic activity and increased secretion of tumor-promoting cytokines in MM-BMSC co-cultures. HuL001 suppressed these ENO1-driven effects. HuL001-pretreated stromal cells also exhibited reduced tumor-supportive activity in a BTZ-resistant MM xenograft model. In addition, HuL001 combined with lenalidomide overcame BTZ resistance in MM. Conclusions: Extracellular ENO1 drives CAF-associated stromal reprogramming in the MM microenvironment through the ENO1\/plasminogen\/plasmin\/TGF-\u03b2 axis. Therapeutic targeting of extracellular ENO1 with HuL001 may disrupt these tumor-supportive stromal activities and help overcome drug resistance in MM.<\/jats:p>","DOI":"10.3390\/cancers18091467","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:15:02Z","timestamp":1777853702000},"page":"1467","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Extracellular Enolase-1 Promotes CAF-Associated Stromal Reprogramming via the Plasmin\/TGF-\u03b2 Axis in Multiple Myeloma"],"prefix":"10.3390","volume":"18","author":[{"given":"I-Che","family":"Chung","sequence":"first","affiliation":[{"name":"Department of Research and Development, HuniLife Biotechnology, Inc., Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tung-Yueh","family":"Chuang","sequence":"additional","affiliation":[{"name":"Department of Research and Development, HuniLife Biotechnology, Inc., Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2329-309X","authenticated-orcid":false,"given":"Yu-Tung","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Research and Development, HuniLife Biotechnology, Inc., Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao-Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Research and Development, HuniLife Biotechnology, Inc., Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9620-5435","authenticated-orcid":false,"given":"Po-Yang","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Research and Development, HuniLife Biotechnology, Inc., Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1255-2067","authenticated-orcid":false,"given":"Wei-Ching","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Research and Development, HuniLife Biotechnology, Inc., Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ta-Tung","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Research and Development, HuniLife Biotechnology, Inc., Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dima, D., Ullah, F., Mazzoni, S., Williams, L., Faiman, B., Kurkowski, A., Chaulagain, C., Raza, S., Samaras, C., and Valent, J. 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