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To overcome T-cell exhaustion, we engineered a CAR T-cell construct (M28z1XXPD1DNR) that incorporates a programmed cell death protein-1 decoy receptor lacking the intracellular signaling domain, which enhances functional persistence. We demonstrate that intraperitoneal (regional) administration of CAR T cells at low doses achieves superior antitumor efficacy, longer survival, and sustained functional persistence, compared with intravenous (systemic) administration. Of note, intraperitoneal treatment also exhibits potency against distant disease sites. These findings provide a strong rationale for clinical translation; we are now conducting a clinical trial (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT06623396\">NCT06623396<\/jats:ext-link>) to evaluate intraperitoneal administration of M28z1XXPD1DNR CAR T cells in patients with gastroesophageal cancer peritoneal carcinomatosis.<\/jats:p>","DOI":"10.1136\/jitc-2025-012292","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T02:46:58Z","timestamp":1757990818000},"page":"e012292","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Intraperitoneal CAR T-cell therapy for peritoneal carcinomatosis from gastroesophageal cancer: preclinical investigations to a phase I clinical trial 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