{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T13:01:37Z","timestamp":1793192497091,"version":"4.5.0"},"reference-count":36,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T00:00:00Z","timestamp":1741824000000},"content-version":"unspecified","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82073750"],"award-info":[{"award-number":["82073750"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473824"],"award-info":[{"award-number":["82473824"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U20A20409"],"award-info":[{"award-number":["U20A20409"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011441","name":"State Key Laboratory for Diagnosis and Treatment of Infectious Diseases","doi-asserted-by":"publisher","award":["Grant No. zz202303"],"award-info":[{"award-number":["Grant No. zz202303"]}],"id":[{"id":"10.13039\/501100011441","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC3403900"],"award-info":[{"award-number":["2023YFC3403900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,2,21]]},"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Clinical trials have demonstrated the efficacy of bispecific antibodies in eliciting potent antitumor responses by redirecting T cells to target cancer cells, particularly for the treatment of hematologic malignancies. However, their efficacy against solid tumors is limited by intratumoral T-cell dysfunction and inadequate persistence. The co-stimulatory domains of 4-1BB, OX40, and CD28 are most widely used in engineering chimeric antigen receptor T-cells to augment T-cell responses.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In this study, we designed three co-stimulatory trispecific T cell-engaging antibodies (TriTCEs) that target Prostate-specific membrane antigen, CD3, and an additional co-stimulatory receptor(OX40, 4-1BB, or CD28). We conducted comparative profiling of the attributes of distinct co-stimulatory signals to T-cell functions in prostate cancer models.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Co-stimulatory trispecific T-cell engagers enhance T-cell activation, proliferation, and display tumor cell-killing activity in vitro. These trispecific antibodies further boosted antitumor activity in humanized mouse xenograft models and increased the infiltration of CD45<jats:sup>+<\/jats:sup> immune cells into solid tumors. Specifically, TriTCE-4-1BB and TriTCE-CD28 selectively promoted the expansion of effector memory T cells and increased the presence of CD4<jats:sup>+<\/jats:sup> T cells more than TriTCE-OX40. T cells stimulated with TriTCE-4-1BB exhibited reduced exhaustion. Furthermore, T cells treated with co-stimulatory trispecific antibodies demonstrated enhanced metabolic activity characterized by increased oxidative phosphorylation and elevated glycolysis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Collectively, incorporating co-stimulatory receptor targeting domains represents a potentially effective strategy to unlock the full therapeutic potential of T-cell-engaging antibodies for the treatment of solid tumors.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-010140","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T08:26:52Z","timestamp":1741854412000},"page":"e010140","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Leveraging T cell co-stimulation for enhanced therapeutic efficacy of trispecific antibodies targeting 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