{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T19:29:00Z","timestamp":1793647740277,"version":"4.5.1"},"reference-count":45,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"unspecified","delay-in-days":29,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,9,3]]},"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Claudin 18.2 (CLDN18.2) is a tight junction protein retained in malignant transformation of gastric cancer (GC) and is a promising therapeutic target. Despite the clinical benefit of zolbetuximab in CLDN18.2-positive tumors, the dynamic expression of CLDN18.2 during chemoimmunotherapy and its implications in the tumor microenvironment (TME) remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a prospective single-arm phase II trial, we evaluated serial tumor biopsies from patients with advanced GC receiving first-line chemotherapy (capecitabine\/oxaliplatin) with sequential pembrolizumab. CLDN18.2 expression was assessed by immunohistochemistry, and integrated molecular analyses\u2014including whole transcriptome, whole exome, and single-cell RNA sequencing\u2014were performed to explore TME alterations and molecular correlates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 57 patients, 40.4% were CLDN18.2-positive at baseline. CLDN18.2 positivity was associated with diffuse-type histology, higher programmed death-ligand 1 (PD-L1) combined positive scores, and an immune-inflamed, stroma-rich TME characterized by enhanced T cell infiltration, transforming growth factor-\u03b2 signaling, and matrix remodeling. Gene set enrichment analyses revealed immune activation and stromal remodeling in CLDN18.2-positive tumors. Single-cell analysis showed increased regulatory T cells and galectin-3-CD44 signaling in CLDN18.2-positive tumors. After one cycle of chemotherapy, CLDN18.2 expression was lost in 40% of initially positive tumors, while 10% of initially negative tumors gained expression\u2014particularly in fibrotic TMEs. Survival outcomes were not significantly different between CLDN18.2-positive and CLDN18.2-negative groups; however, patients negative for both CLDN18.2 and PD-L1 showed poorer prognosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CLDN18.2 expression is dynamically regulated during chemoimmunotherapy and is associated with a distinct immunosuppressive and fibrotic TME. These findings highlight the importance of repeated biomarker assessment and suggest potential combinatorial therapeutic strategies targeting both epithelial and stromal compartments in GC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04249739\">NCT04249739<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012683","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T06:06:02Z","timestamp":1759212362000},"page":"e012683","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["Dynamic modulation of claudin18.2 expression and remodeling of the tumor microenvironment in gastric cancer during chemo-immunotherapy"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct04249739","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04249739","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Sung Hee","family":"Lim","sequence":"first","affiliation":[{"name":"Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul, The Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kuwata","sequence":"additional","affiliation":[{"name":"Department of Pathology and Clinical Laboratories, National Cancer Center-Hospital East, Kashiwa, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9575-7952","authenticated-orcid":false,"given":"Minae","family":"An","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Department of 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