{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T04:26:07Z","timestamp":1793939167309,"version":"4.8.0"},"reference-count":24,"publisher":"American Society of Hematology","issue":"24","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,11]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Glutamine dependence of cancer cells reduces local glutamine availability, which hinders antitumor T-cell functionality and facilitates immune evasion. We thus speculated that glutamine deprivation might be limiting efficacy of chimeric antigen receptor (CAR) T-cell therapies in patients with cancer. We have seen that antigen-specific T cells are unable to proliferate or produce interferon gamma (IFN-\u03b3) in response to antigen stimulation when glutamine concentration is limited. Using multiple myeloma (MM) as a glutamine-dependent disease model, we found that murine CAR T cells selectively targeting B-cell maturation antigen (Bcma) in MM cells were sensitive to glutamine deprivation. However, CAR T cells engineered to increase glutamine uptake by expression of the glutamine transporter Asct2 exhibited enhanced proliferation and responsiveness to antigen stimulation, increased production of IFN-\u03b3, and heightened cytotoxic activity, even under conditions of low glutamine concentration. Mechanistically, Asct2 overexpression reprogrammed the metabolic fitness of CAR T cells by upregulating the mechanistic target of rapamycin complex 1 gene signature, modifying the solute carrier transporter repertoire, and improving both basal oxygen consumption rate and glycolytic function, thereby enhancing CAR T-cell persistence in vivo. Accordingly, expression of Asct2 increased the efficacy of Bcma-CAR T cells in syngeneic and genetically engineered mouse models of MM, which prolonged mouse survival. In patients, higher-level expression of ASCT2 by MM cells predicted poor outcome to combined immunotherapy and BCMA-CAR T-cell therapy. Our results indicate that reprogramming glutamine metabolism may enhance antitumor CAR T-cell functionality in MM. This approach may also be effective for other cancers that depend on glutamine as a key energy source and metabolic hallmark.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024027496","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T18:10:10Z","timestamp":1758305410000},"page":"2931-2944","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":27,"title":["Reprogramming glutamine metabolism enhances\n                    <i>BCMA<\/i>\n                    -CAR T-cell fitness and therapeutic efficacy in multiple myeloma"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5250-8437","authenticated-orcid":false,"given":"Flor","family":"Navarro","sequence":"first","affiliation":[{"name":"1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7122-5475","authenticated-orcid":false,"given":"Teresa","family":"Lozano","sequence":"additional","affiliation":[{"name":"1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Fuentes-Garc\u00eda","sequence":"additional","affiliation":[{"name":"1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of Navarra, Navarra Institute for Health Research, CIBERONC, Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"S\u00e1nchez-Moreno","sequence":"additional","affiliation":[{"name":"1Immunology and Immunotherapy Program, Center for Applied Medical Research, Cancer Center University of 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