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In this study, we investigated the co-evolutionary dynamics between CAR-T cells and the immune microenvironment in myeloma patients undergoing anti-BCMA CAR-T cell therapy at single-cell resolution. Our findings highlight the transformative impact of CAR-T cell treatment on the endogenous T cell landscape. We identify a novel transitional CD8\u2009+\u2009T cell population that is predictive of poor treatment outcomes. The emergence of this population coincides with the depletion of the endogenous T cell repertoire and compositional evolution of functional T cell subsets. These changes in the endogenous T cell compartment induced by CAR-T cell therapy may contribute to inadequate immune capacity and tumor control. Our findings highlight the potential of targeting TIM3\/GAL9 interactions to mitigate T cell exhaustion, apoptosis and lack of persistence, offering promising avenues for optimizing T cell-based cancer immunotherapies. We provide a framework for assessing and manipulating the \u2018mileage\u2019 of the immune system as predictive marker and therapeutic opportunity to prevent repeated immunotherapies from becoming increasingly less successful, even when targeting distinct antigens.<\/jats:p>","DOI":"10.1038\/s41375-025-02766-5","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T17:02:13Z","timestamp":1758301333000},"page":"3004-3014","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The endogenous T cell landscape is reshaped by CAR-T cell therapy and predicts treatment response in multiple myeloma"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4380-9673","authenticated-orcid":false,"given":"Julia","family":"Frede","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia C.","family":"Poller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayleen","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Stuart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noori","family":"Sotudeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Havig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klothilda","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6633-1468","authenticated-orcid":false,"given":"Caroline R. 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Blood. 2021;137:323\u201335.","journal-title":"Blood"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02766-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02766-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02766-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T09:10:51Z","timestamp":1763629851000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02766-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,19]]},"references-count":48,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["2766"],"URL":"https:\/\/doi.org\/10.1038\/s41375-025-02766-5","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,19]]},"assertion":[{"value":"26 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 July 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This project was supported by grants from Bristol Myers Squibb. S.M.K. is an employee of Bristol Myers Squibb. N.M. was an employee of Bristol Myers Squibb at the time the study was performed. PA is currently employed by Union Chimique Belge (UCB).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with relevant guidelines and regulations. The KarMMa-2 (NCT03601078) and KarMMa-3 (NCT03651128) clinical trials that collected the patient samples used in this study were approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) at each participating center and were conducted in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and the Declaration of Helsinki. Written informed consent was obtained from all participants at the time of original sample collection. The Dana-Farber Cancer Institute Institutional Review Board (DFCI IRB) reviewed the present study and determined that it does not involve human subjects research (protocols 19-511 and 19-694). No identifiable images from human research participants are included in this publication.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}