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However, therapy-induced senescence (TIS) has been identified as a novel resistance mechanism, potentially exacerbating immunosuppression and impairing CAR-T cell function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Raji and SU-DHL-2 cells were treated with 40 nM doxorubicin (Dox) for 72\u00a0h to induce TIS, and CCR7 was inhibited with 10\u00a0\u00b5g\/mL Cap-100. Cellular senescence was assessed by SA-\u03b2-Gal staining and flow cytometry; proliferation and apoptosis by CCK-8 and Annexin V\/PI, respectively. CAR-T cytotoxicity was evaluated via flow cytometry. CCR7 expression on T cells from B-NHL patients and healthy controls was measured. Lentiviral transduction regulated CCR7 expression; protein expression and interactions were analyzed by Western blot and Co-IP. NF-\u03baB and ARHGAP\/RhoA pathways were inhibited using GS143 and Y27632, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CCR7 overexpression enhanced SASP, while knockdown attenuated it. In the Dox-induced TIS model, KMT2D decreased, whereas H3K9me3, CCR7, and LGALS9 increased; CCR7 inhibition reversed these changes. Cap-100 improved CD19 CAR T killing by alleviating exhaustion in co-culture. Mechanistically, Cap-100 stabilized I\u03baB\u03b1 to inhibit NF\u03baB, and inhibition of NF\u03baB or ROCK reversed pro-senescence. Cap-100 reduced T cell proliferation but did not affect apoptosis or exhaustion. Clinically, CCR7 was lower on T cells from B NHL patients than healthy controls, and higher CCR7 correlated with better T cell quality. Transcriptomics showed Dox activated TIM3\/Galectin 9 and PD- 1\/PD-L1 pathways, while Dox\u2009+\u2009Cap-100 suppressed them. Co-IP confirmed interactions among CCR7, KMT2D, and LGALS9. Collectively, Dox induced TIS to upregulate CCR7, increasing SASP and LGALS9, which interacted with TIM-3, causing immune cell exhaustion and reducing killing efficiency; CCR7 blockade reversed this state and enhanced cytotoxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Our findings demonstrate that blockade of KMT2D-CCR7-mediated senescence enhances CD19 CAR-T cell anti-tumor activity in B-NHL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12916-026-05030-4","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T13:38:30Z","timestamp":1782481110000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting CCR7-KMT2D enhances CAR-T cell efficacy by suppressing therapy-induced senescence in B-cell non-Hodgkin lymphoma"],"prefix":"10.1186","volume":"24","author":[{"given":"Jinlan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keke","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanjia","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanyue","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nengneng","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqiu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zelin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziye","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianshan","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaohong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhimin","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Furun","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"5030_CR1","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1111\/bjh.16461","volume":"189","author":"ML Moleti","year":"2020","unstructured":"Moleti ML, Testi AM, Fo\u00e0 R. 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All methods were performed according to relevant guidelines and regulations. Informed consent was obtained from all patients enrolled in the study. All animal experiments were conducted in accordance with the guidelines of the Institute of Health Sciences at the Hefei Comprehensive National Science Center and were approved by the Institute\u2019s Committee on Animal Welfare and Ethics (Approval No: I H M -AP-2026-042).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"492"}}