{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T14:31:15Z","timestamp":1785335475499,"version":"3.55.0"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373279"],"award-info":[{"award-number":["82373279"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Tianjin Key Medical Discipline Construction Project","award":["TJYXZDXK-3-003A"],"award-info":[{"award-number":["TJYXZDXK-3-003A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Precursor exhausted and terminally exhausted T cells (Tpex and Tex) are associated with immune checkpoints; T-cell checkpoint blockade may improve patient survival. We assessed cytotoxic activity and PD-1\/TIM-3 expressions of CD3+CD8+CD56+ T cells (NK-like T) in cytokine-induced killer (CIK) cells across exhaustion states. We grouped the NK-like T cells into 3 based on TOX and TCF1 expressions: TOX\u2212TCF1+ (memory-like NK-like T), TOX+TCF1+ (NK-like Tpex), and TOX+TCF1\u2212 (NK-like Tex). The proportion of NK-like Tpex cells among the CIK cells was the highest (&amp;gt;90%) after culture. TIM-3 and PD-1 expression were high in NK-like Tpex but low in NK-like Tex cells. However, TIM-3 expression was higher than PD-1 expression in CIK cells, suggesting that combining CIK cells and TIM-3 inhibitors may have better effects. Perforin, granzyme B, DNAM-1, and NKG2D, which are cytotoxicity biomarkers, were more expressed in NK-like Tpex than in NK-like Tex cells, which implies that NK-like Tpex may still has a strong cytotoxic effect. The CD4\u207a T cell counts and TIM-3 expression level in the NK-like Tpex cells were positively correlated. CD4\u207a T cells may actively sustain progenitor exhaustion, but the mechanisms are unknown. In vitro cytotoxicity assays confirmed that CIK cell-mediated tumor cytotoxicity was significantly enhanced by TIM-3 than by PD-1 blockade. Furthermore, tumor cytotoxicity was greater for CIK cell cultures with higher than those with lower CD4\u207a T cell counts following TIM-3 blockade. This work demonstrates CD4\u207aT cell modulation of progenitor exhaustion in CIK cells and positions TIM-3 blockade to rescue their antitumor potential.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf180","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T13:03:28Z","timestamp":1765544608000},"source":"Crossref","is-referenced-by-count":1,"title":["Progenitor-predominant exhaustion in cytokine-induced killers reveals TIM-3 as a superior target for enhancing cytokine-induced killer cytotoxicity"],"prefix":"10.1093","volume":"118","author":[{"given":"Jian","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer , Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060 ,","place":["China"]},{"name":"Tianjin\u2019 s Clinical Research Center for Cancer , Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060 ,","place":["China"]},{"name":"Key Laboratory of Cancer Immunology and Biotherapy , Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer , Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060 ,","place":["China"]},{"name":"Tianjin\u2019 s Clinical Research Center for Cancer , Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060 ,","place":["China"]},{"name":"Key Laboratory of Cancer Immunology and Biotherapy , Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer , Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060 ,","place":["China"]},{"name":"Tianjin\u2019 s Clinical Research Center for Cancer , Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060 ,","place":["China"]},{"name":"Key Laboratory of Cancer Immunology and Biotherapy , Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhou","sequence":"additional","affiliation":[{"name":"Tianjin\u2019 s Clinical Research Center for Cancer , Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060 ,","place":["China"]},{"name":"Department of Biotherapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer , Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060 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