{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T16:41:25Z","timestamp":1788280885761,"version":"build-2803163510"},"reference-count":82,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001321","name":"National Research Foundation","doi-asserted-by":"publisher","award":["RS-2025-25442355"],"award-info":[{"award-number":["RS-2025-25442355"]}],"id":[{"id":"10.13039\/501100001321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematological malignancies, yet its efficacy in solid tumors is severely limited by the metabolically hostile tumor microenvironment (TME). Within this landscape, CAR-T cells undergo rapid functional exhaustion driven by mitochondrial dysfunction and metabolic insufficiency. This mini-review synthesizes emerging mitochondrial engineering strategies designed to restore metabolic fitness and persistence. We first examine the newly identified metabolic-epigenetic axis, where the pathological mitochondrial translocation of\n                    <jats:italic>P4HA1<\/jats:italic>\n                    and the concomitant accumulation of oncometabolite succinate lock T cells in an exhausted state, and discuss how targeting this pathway restores progenitor subsets. Furthermore, we explore genetic reprogramming approaches, including \u201cEnvirotune\u201d platforms that couple hypoxia-sensing elements (HRE) with enhanced glutamine transport (\n                    <jats:italic>SLC38A2<\/jats:italic>\n                    ), and CRISPR-identified targets such as\n                    <jats:italic>RHOG<\/jats:italic>\n                    and\n                    <jats:italic>FAS<\/jats:italic>\n                    that prevent fratricide and apoptosis to preserve effector pools. Finally, we highlight the frontier of organelle medicine, focusing on intercellular mitochondrial transfer via tunneling nanotubes (TNTs) mediated by Talin-2, and emerging computational strategies to detect mitochondrial hijacking risk. By integrating these metabolic interventions, next-generation CAR-T cells can be engineered to overcome the TME\u2019s metabolic barriers, transforming them from transient effectors into long-lived, highly effective therapeutic agents.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1822668","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:56:14Z","timestamp":1778219774000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Supercharging the metabolic engine: mitochondrial engineering strategies for CAR-T persistence in solid tumors"],"prefix":"10.3389","volume":"17","author":[{"given":"Soohyun","family":"Chun","sequence":"first","affiliation":[{"name":"Translational-Transdisciplinary Research Center, Medical Science Research Institute, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University","place":["Seoul, Republic of Korea"]},{"name":"Department of Medicine, Kyung Hee University College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanghyeon","family":"Yu","sequence":"additional","affiliation":[{"name":"Translational-Transdisciplinary Research Center, Medical Science Research Institute, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University","place":["Seoul, Republic of Korea"]},{"name":"Department of Biomedical Science and Technology, Graduate School, Kyung Hee University","place":["Seoul, Republic of Korea"]},{"name":"Center for Space Biomedical Science, NEXUS Institute, Kyung Hee University","place":["Yongin, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Gu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Translational-Transdisciplinary Research Center, Medical Science Research Institute, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University","place":["Seoul, Republic of Korea"]},{"name":"Department of Medicine, Kyung Hee University College of Medicine","place":["Seoul, Republic of Korea"]},{"name":"Department of Biomedical Science and Technology, Graduate School, Kyung Hee University","place":["Seoul, Republic of Korea"]},{"name":"Center for Space Biomedical Science, NEXUS Institute, Kyung Hee University","place":["Yongin, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.omto.2022.03.009","article-title":"CAR T cell therapy and the tumor 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