{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:28:41Z","timestamp":1789691321894,"version":"4.0.1"},"reference-count":21,"publisher":"The Microbiological Society of Korea","issue":"1","license":[{"start":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T00:00:00Z","timestamp":1769817600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013129","name":"Ministry of SMEs and Startups","doi-asserted-by":"publisher","award":["RS-2024-00508867"],"award-info":[{"award-number":["RS-2024-00508867"]}],"id":[{"id":"10.13039\/501100013129","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chungbuk Regional Innovation System & Education Center"},{"DOI":"10.13039\/501100002701","name":"Ministry of Education","doi-asserted-by":"publisher","award":["2025-RISE-11-014-03"],"award-info":[{"award-number":["2025-RISE-11-014-03"]}],"id":[{"id":"10.13039\/501100002701","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["jmicrobiol.or.kr"],"crossmark-restriction":true},"short-container-title":["Journal of Microbiology"],"published-print":{"date-parts":[[2026,1,31]]},"abstract":"<jats:p>Chimeric antigen receptor (CAR)-T cell therapy holds significant potential for the treatment of solid tumors. However, immune suppression and tumor-specific barriers limit its application. Claudin 18.2 (CLDN18.2), a gastric lineage-specific tight junction protein highly expressed in gastric and pancreatic cancers, is a promising therapeutic target. In this study, we aimed to develop a next-generation tri-cistronic CLDN18.2-directed CAR-T cell platform that integrates a programmed cell death protein 1 (PD-1)\/CD28 chimeric switch receptor with cyclophilin A (CypA). This platform sought to counteract PD-1\u2013mediated immunosuppression and enhance T-cell activation and persistence. We generated CLDN18.2 CAR-T cells incorporating costimulatory inducible T-cell costimulator (ICOS) domains using lentiviral vector-based recombinant engineering. We further evaluated their cytokine release, cytotoxic activity, and safety profiles. In vitro, tri-cistronic CAR-T cells exhibited markedly increased interferon \u03b3 and tumor necrosis factor \u03b1 secretion and enhanced cytotoxicity against CLDN18.2-positive gastric cancer cells compared with conventional CAR-T constructs. In vivo, these cells showed superior antitumor efficacy and sustained tumor regression without observable toxicity in xenograft gastric cancer models. Collectively, these findings demonstrate that the integration of PD-1\/CD28 signaling and CypA within a tri-cistronic framework significantly reinforces CAR-T cell functionality and durability. This suggests strong clinical potential as a next-generation immunotherapy for solid tumors.<\/jats:p>","DOI":"10.71150\/jm.2510017","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T05:47:33Z","timestamp":1769579253000},"page":"e2510017","update-policy":"https:\/\/doi.org\/10.71150\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Development of tri-cistronic CLDN18.2 CAR-T cells incorporating PD-1\/CD28 switch and cyclophilin A for enhanced solid tumor immunotherapy"],"prefix":"10.71150","volume":"64","author":[{"given":"Heon Ju","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seo Jin","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Hee","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi Hee","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bu Yeon","family":"Heo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaeyul","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoona","family":"Noh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihoon","family":"Nah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4586","reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-022-04657-9"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.07.056"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00499-z"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1038\/83784"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.3ru0317-090rr"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1186\/s12861-018-0167-3"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118300"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1172\/jci166028"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1056\/nejmra1706169"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.107470"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1007\/s12275-024-00133-0"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-020-07180-x"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1805-z"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-15-1433"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-022-00417-w"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aau5907"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.687822"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.33590\/emjhematol\/20-00079"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(03)00207-3"},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.1007\/3-540-29714-6_3"},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.3407"}],"container-title":["Journal of Microbiology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/jmicrobiol.or.kr\/upload\/pdf\/jm-2510017.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/jmicrobiol.or.kr\/journal\/view.php?doi=10.71150\/jm.2510017","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/jmicrobiol.or.kr\/upload\/pdf\/jm-2510017.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T05:47:49Z","timestamp":1769579269000},"score":1,"resource":{"primary":{"URL":"http:\/\/jmicrobiol.or.kr\/journal\/view.php?doi=10.71150\/jm.2510017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,31]]},"references-count":21,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"URL":"https:\/\/doi.org\/10.71150\/jm.2510017","relation":{},"ISSN":["1225-8873","1976-3794"],"issn-type":[{"value":"1225-8873","type":"print"},{"value":"1976-3794","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,31]]},"assertion":[{"value":"2025-10-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-31","order":2,"name":"published","label":"Published online","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-31","order":3,"name":"published","label":"Print publication","group":{"name":"publication_history","label":"Publication History"}}]}}