{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:59:27Z","timestamp":1790189967478,"version":"4.1.0"},"reference-count":67,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"39","funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["815379"],"award-info":[{"award-number":["815379"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["101140394"],"award-info":[{"award-number":["101140394"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Adelis Foundation"},{"name":"Avatalion Family Award"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,9,25]]},"abstract":"<jats:p>\n                    T cell receptor (TCR) gene transfer is a promising approach for cancer immunotherapy, but its efficacy is limited by mispairing of TCR chains, which reduces surface expression and may generate off-target specificities. We applied the PROSS and FuncLib algorithms to engineer human TCR constant regions for improved stability and preferential pairing. After several screening rounds, we identified a variant, termed structurally enhanced TCR (SET), that exhibited markedly enhanced surface expression, functional avidity, and reduced mispairing. SET-expressing T cells secreted higher cytokine levels, displayed increased activation, and mediated superior cytotoxicity. Notably, SET demonstrated function in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and mediated potent tumor control in xenograft models, significantly delaying tumor growth and improving survival. SET\u2019s benefits were reproducible across six different TCRs, supporting its broad applicability. These findings highlight the potential of rational design to improve the potency of TCR-based therapies.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeb9189","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T17:59:49Z","timestamp":1790186389000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Computational design of optimized and preferentially paired human TCR constant regions for improved T cell function"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4944-5222","authenticated-orcid":true,"given":"Maria","family":"Radman","sequence":"first","affiliation":[{"name":"The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5396-8643","authenticated-orcid":true,"given":"Astar","family":"Shamul-Raybi","sequence":"additional","affiliation":[{"name":"The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jake","family":"Parker","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3177-7560","authenticated-orcid":true,"given":"Sarel J.","family":"Fleishman","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0619-5959","authenticated-orcid":true,"given":"Cyrille J.","family":"Cohen","sequence":"additional","affiliation":[{"name":"The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1537-0"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1994.tb06772.x"},{"key":"e_1_3_2_4_2","first-page":"253","article-title":"Adoptive T-cell immunotherapy: Perfecting self-defenses","volume":"113","author":"Zur R. T.","year":"2022","unstructured":"R. T. Zur, G. Adler, K. Shamalov, Y. Tal, C. Ankri, C. J. Cohen, Adoptive T-cell immunotherapy: Perfecting self-defenses. Exp. Suppl. 113, 253\u2013294 (2022).","journal-title":"Exp. Suppl."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1335424"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00809-z"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abh1962"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01621-1"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI82416"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00582"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.9.6116"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12441-w"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzq113"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1005802107"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-1450"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902047"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902055"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-3986"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-05-023069"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103020"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20082487"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301253"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2011.104"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8385"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2005.12.009"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.11.7736"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.1.391"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.19095"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2017.6206"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2019.01.007"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.06.012"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.08.033"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1007207"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1129003"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16231-7"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2022.281628"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2024012967"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.9.5799"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.6.3287"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20042323"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1108422109"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.103035"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2314999121"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-01225-1"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03109-0"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-1280"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature21405"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-019-0409-0"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aba7365"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05531-1"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.10.001"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-025-00927-0"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac887"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.08.041"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-023-02561-1"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1032403"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1251102"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0102-70"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203085"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0721-y"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-23-0823"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1536868"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11869-4"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.09.010"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-008434"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1477929"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.9.6548"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.1.309"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aeb9189","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:02:06Z","timestamp":1790186526000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aeb9189"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":67,"journal-issue":{"issue":"39","published-print":{"date-parts":[[2026,9,25]]}},"alternative-id":["10.1126\/sciadv.aeb9189"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aeb9189","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"assertion":[{"value":"2025-09-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeb9189"}}