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Indoleamine 2,3\u2010dioxygenase 1 (IDO), an enzyme that metabolizes tryptophan (Trp) to kynurenine (Kyn), plays an immunosuppressive role in the TME. We previously reported that a high Kyn\/Trp ratio was associated with poor prognosis in lenalidomide\u2010treated refractory\/relapsed MM patients and that IDO expression in stromal cells was upregulated by co\u2010culture with MM cells. Here, we analyzed the mechanism through which MM cells upregulate IDO in stromal cells and aimed to identify compounds that inhibit IDO upregulation. Two MM cell lines, XG\u20107 and IM\u20109, upregulated IDO in stromal cells both directly and indirectly. These two MM cell lines also upregulated programmed cell death ligand 1 (PD\u2010L1) in stromal cells, which was closely related to IDO upregulation. RNA sequencing analysis revealed that cytokine signaling pathways were commonly upregulated in stromal cells co\u2010cultured with these two MM cell lines. In stromal cells co\u2010cultured with MM cells, signal transducer and activator of transcription 1 (STAT1) and nuclear factor\u2010\u03baB (NF\u2010\u03baB) p65 was phosphorylated, and interferon regulatory factor 1 (IRF1), which binds to the IDO promoter region, was strongly upregulated. This IDO and IRF1 upregulation were abolished by Janus kinase (JAK) inhibitor. In addition, stromal cells with knockout of\n                    <jats:italic>IRF1<\/jats:italic>\n                    showed little upregulation of IDO when co\u2010cultured with MM cells. These results suggest that the JAK\u2013STAT1\u2013NF\u2010\u03baB\u2013IRF1 signaling pathway may be involved in IDO upregulation. JAK inhibitors may improve the TME in MM and positively influence immunotherapy outcomes.\n                  <\/jats:p>","DOI":"10.1111\/cas.70255","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T04:34:16Z","timestamp":1764218056000},"page":"325-334","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting Overexpressed IDO in Stromal Cells as a Potential Therapeutic Strategy in Multiple Myeloma"],"prefix":"10.1111","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4341-9563","authenticated-orcid":false,"given":"Toru","family":"Ebina","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology Nagoya City University Graduate School of Medical Sciences  Nagoya Japan"},{"name":"Department of Gastroenterology, Hematology and Clinical Immunology Hirosaki University Graduate School of Medicine  Hirosaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9617-486X","authenticated-orcid":false,"given":"Masaki","family":"Ri","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Nagoya City University Graduate School of Medical Sciences  Nagoya Japan"},{"name":"Department of Blood Transfusion and Cell Therapy Nagoya City University Hospital  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Marumo","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Nagoya City University Graduate School of Medical Sciences  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Nagoya City University Graduate School of Medical Sciences  Nagoya 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Hematology and Cell Therapy Aichi Cancer Center Hospital  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arisa","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Nagoya City University Graduate School of Medical Sciences  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiori","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Nagoya City University Graduate School of Medical Sciences  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomotaka","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Nagoya City University Graduate School of Medical Sciences  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Narita","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology 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