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Adoptive DNT therapy has emerged as a promising cancer immunotherapy due to its potent cytotoxic function and lack of graft-versus-host-disease. However, the intrinsic mechanisms regulating DNT antitumor functions remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Signaling lymphocytic activation molecule factor 7 (SLAMF7) expression in murine and human DNT were evaluated. The antitumor activities were compared between SLAMF7\n                      <jats:sup>+<\/jats:sup>\n                      and SLAMF7\n                      <jats:sup>\u2212<\/jats:sup>\n                      DNT both\n                      <jats:italic>in vivo<\/jats:italic>\n                      and\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Further, metabolomics analysis was performed to reveal the underlying mechanism by which SLAMF7 promotes DNT antitumor cytotoxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The expression of SLAMF7 was markedly increased on DNT upon activation. SLAMF7\n                      <jats:sup>+<\/jats:sup>\n                      DNT exhibited superior antitumor capacity both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      compared with SLAMF7\n                      <jats:sup>\u2212<\/jats:sup>\n                      DNT. Mechanistically, SLAMF7 enhanced antitumor activity through ligand-independent and ligand-dependent dual manners. Firstly, SLAMF7 could upregulate GPT2\/SLC1A5-mediated glutamine metabolism by activating ERK signaling pathway in DNT, thereby supporting mitochondrial fitness, increasing ATP production, enhancing the expression of effector molecules such as granzyme B and perforin, and promoting antitumor activity of DNT against tumor cells independent of homotypic ligand-receptor interactions. Secondly, DNT showed superior antitumor cytotoxicity against SLAMF7-expressing tumor cells because SLAMF7-SLAMF7 interaction between DNT and SLAMF7-expressing tumor cells promoted DNT cell degranulation. Furthermore, SLAMF7 was also highly expressed in human DNT, and its dual antitumor roles in human DNT were also validated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>SLAMF7 is a key regulator of DNT-mediated cytotoxicity and a promising target for improving DNT cell function in cancer therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-025-03570-w","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T07:21:42Z","timestamp":1761808902000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SLAMF7 promotes TCR\u03b1\u03b2+ double negative T cell antitumor activity through enhancing glutamine metabolism"],"prefix":"10.1186","volume":"44","author":[{"given":"Nan","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peiyang","family":"Fang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Longyang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaotong","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Buer","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zihan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaonan","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangyong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"3570_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.816005","volume":"13","author":"Z Wu","year":"2022","unstructured":"Wu Z, Zheng Y, Sheng J, Han Y, Yang Y, Pan H, et al. 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All animal experiments were performed in accordance with the guidelines of the Institutional Animal Care and Ethics Committee of Beijing Chao-Yang Hospital (20-2042).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"D.Z., G.S., and N.X. are inventors on a patent application related to the enhancement of DNT cytotoxicity by regulating SLAMF7. The other authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"297"}}