{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:39:57Z","timestamp":1792798797722,"version":"4.5.0"},"reference-count":40,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"unspecified","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Shanghai Shenkang Hospital","award":["SHDC2020CR2070B"],"award-info":[{"award-number":["SHDC2020CR2070B"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82400243, 82370209"],"award-info":[{"award-number":["82400243, 82370209"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Collaborative Academic Innovation Project of Shandong Cancer Hospital","award":["FC009"],"award-info":[{"award-number":["FC009"]}],"id":[{"id":"https:\/\/ror.org\/01413r497","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,5,8]]},"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells within the bone marrow (BM) microenvironment, which significantly contributes to immune suppression of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Our previous research identified that dysregulation of the IRE1\u03b1-XBP1s-SLC38A2 axis leads to decreased glutamine uptake and senescence of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in MM. However, the underlying mechanisms of T-cell senescence remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Single-cell RNA sequencing was used to analyze mitochondrial function in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in MM. The effects of XBP1s and SLC38A2 on mitochondrial reactive oxygen species (mtROS) were evaluated by flow cytometry under loss-of-function experiments. An IRE1\u03b1 inhibitor (17#) was administered to explore its effects on T-cell senescence and MM cell growth. RNA sequencing was employed to disclose pathway alterations in T cells treated with 17#. The Vk*MYC mouse model was used to assess the impact of 17# on CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell senescence and anti-myeloma effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      BM-derived CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells from patients with MM exhibited downregulated expressions of genes critical for glutamine transport (SLC38A2), mitochondrial respiratory chain, and ATP synthesis, while genes associated with ROS were upregulated. Suppression of XBP1s in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells resulted in decreased mtROS levels, whereas inhibition of SLC38A2 increased mtROS levels. Compound 17# significantly reduced senescence marker KLRG1 expression and increased perforin expression in nutrient-deprived BM CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells from healthy donors and in BM CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells from patients with MM, while promoting T-cell proliferation. Importantly, 17# did not impair the viability of peripheral blood mononuclear cells from healthy donors or alter the immune phenotypes of healthy CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. The NPR2-cGMP-PKG pathway was activated by IRE1\u03b1 inhibition in restoring T-cell function. Furthermore, 17# exhibited direct inhibitory effects on MM cells. In Vk*MYC mouse model, 17# decreased mtROS levels in BM CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, reduced the proportion of senescent (KLRG1\n                      <jats:sup>+<\/jats:sup>\n                      CD57\n                      <jats:sup>+<\/jats:sup>\n                      CD28\n                      <jats:sup>\u2212<\/jats:sup>\n                      ) T cells, and resulted in a lower tumor burden.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Inhibiting IRE1\u03b1 represents a promising strategy to reverse the senescence of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells by mitigating mtROS production. This dual mechanism not only rejuvenates T cells but also directly targets myeloma cells, offering a novel therapeutic approach for MM treatment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-011044","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T01:35:14Z","timestamp":1748309714000},"page":"e011044","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Dual roles of IRE1\u03b1 inhibition in reversing mitochondrial ROS-induced CD8\n                    <sup>+<\/sup>\n                    T-cell senescence and exerting direct antitumor effects in multiple myeloma"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1199-5755","authenticated-orcid":false,"given":"Yike","family":"Wan","sequence":"first","affiliation":[{"name":"Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengping","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fajun","family":"Nan","sequence":"additional","affiliation":[{"name":"The Chinese National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honghui","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"2026052723002851000_13.5.e011044.1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1568009617666170214102301","article-title":"Multiple Myeloma and the immune microenvironment","volume":"17","author":"Kawano","year":"2017","journal-title":"CCDT"},{"key":"2026052723002851000_13.5.e011044.2","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0000000000000615"},{"key":"2026052723002851000_13.5.e011044.3","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2020.606368","article-title":"Harnessing the Immune System Against Multiple Myeloma: Challenges and Opportunities","volume":"10","author":"Yamamoto","year":"2020","journal-title":"Front Oncol"},{"key":"2026052723002851000_13.5.e011044.4","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s00281-019-00744-5","article-title":"CD8+ T cell exhaustion","volume":"41","author":"Kurachi","year":"2019","journal-title":"Semin Immunopathol"},{"key":"2026052723002851000_13.5.e011044.5","doi-asserted-by":"crossref","first-page":"216171","DOI":"10.1016\/j.canlet.2023.216171","article-title":"Single-cell RNA sequencing reveals XBP1-SLC38A2 axis as a metabolic regulator in cytotoxic T lymphocytes in multiple myeloma","volume":"562","author":"Wan","year":"2023","journal-title":"Cancer Lett"},{"key":"2026052723002851000_13.5.e011044.6","doi-asserted-by":"crossref","first-page":"63","DOI":"10.2131\/jts.42.63","article-title":"Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines","volume":"42","author":"Tungkum","year":"2017","journal-title":"J Toxicol Sci"},{"key":"2026052723002851000_13.5.e011044.7","doi-asserted-by":"crossref","first-page":"440","DOI":"10.48095\/ccko2023440","article-title":"The endoplasmic reticulum and its signaling pathways - 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