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The review also summarizes an expanding pipeline including high-affinity antibodies, bispecific antibodies, antibody-drug conjugates, and CAR-T approaches, positioning CLDN18.2-targeted therapy for multiple disease stages and cancer 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is CLDN18.2 considered a therapeutic target in advanced gastric cancer?","Question",{"text":63,"@type":64},"CLDN18.2 is selectively expressed in normal gastric epithelium and is widely retained during tumorigenesis, becoming accessible on the tumor surface after cellular disruption, which supports targeted therapies such as monoclonal antibodies.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What evidence supports CLDN18.2 targeting with zolbetuximab?",{"text":68,"@type":64},"The SPOTLIGHT and GLOW phase III trials evaluated zolbetuximab with first-line chemotherapy in HER2-negative and CLDN18.2-positive advanced gastric cancer, showing improved clinical outcomes and manageable safety.",{"name":70,"@type":61,"acceptedAnswer":71},"What other CLDN18.2-directed treatment strategies are discussed beyond zolbetuximab?",{"text":72,"@type":64},"The review highlights a pipeline including high-affinity anti-CLDN18.2 monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T-cell approaches evaluated in early-phase studies.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},354852,1790230116,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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[https://doi.org/10.5230/jgc.2026.26.e10](https://doi.org/10.5230/jgc.2026.26.e10)[ ](https://doi.org/10.5230/jgc.2026.26.e10)pISSN 2093-582X·eISSN 2093-5641  \nReview Article  \nReceived: Dec 9, 2025  \nRevised: Dec 18, 2025  \nAccepted: Dec 18, 2025  \nPublished online: Dec 31, 2025  \nCorrespondence to  \nIzuma Nakayama  \nDepartment of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa 277-8577, Japan.  \nEmail: [iznakaya@east.ncc.go.jp](iznakaya@east.ncc.go.jp)  \n*Fei Zhang and Ukyo Okazaki contributed equally to this work.  \nCopyright © 2026. Korean Gastric Cancer Association  \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ([https://](https://)[ ](https://)[creativecommons.org/licenses/by-nc/4.0](creativecommons.org/licenses/by-nc/4.0)) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.  \nORCID iDs  \nUkyo Okazaki  [https://orcid.org/0009-0003-4097-6120](https://orcid.org/0009-0003-4097-6120)[ ](https://orcid.org/0009-0003-4097-6120)Izuma Nakayama  [https://orcid.org/0000-0003-4987-1934](https://orcid.org/0000-0003-4987-1934)[ ](https://orcid.org/0000-0003-4987-1934)Kohei Shitara  [https://orcid.org/0000-0001-5196-3630](https://orcid.org/0000-0001-5196-3630)  \nConflict of Interest  \nNo potential conflict of interest relevant to this article was reported.  \nCLDN18.2 in Gastric Cancer: Current Therapeutic Landscape and Future Perspectives  \nFei Zhang 1,*, Ukyo Okazaki  2,*, Izuma Nakayama  2, Kohei Shitara  2  \n1Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China 2Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan  \nABSTRACT  \nClaudin 18.2 (CLDN18.2), a tight junction protein selectively expressed in normal gastric epithelium and widely retained during carcinogenesis, has emerged as a promising therapeutic target for advanced gastric cancer (AGC) . SPOTLIGHT and GLOW trials evaluated the anti-CLDN18.2 monoclonal antibody (mAb) zolbetuximab in combination with first-line chemotherapy, and established CLDN18.2 as a therapeutic target, initiating a paradigm shift toward a biomarker-driven treatment approach in AGC. In addition, from zolbetuximab toa diverse pipeline of promising high-affinity mAbs, bispecific antibodies, antibody-drug conjugates and chimeric antigen receptor T cells, this target has established a new and highly effective therapeutic avenue for CLDN18.2-expressing AGC. Therefore, as research progresses, CLDN18.2-targeted therapy is poised to become a cornerstone of treatment across multiple disease stages and cancer types. This review describes the biological role ofCLDN18.2 in normal gastric epithelium and gastric carcinogenesis and summarizes the current therapeutic landscape and future perspectives targeting CLDN18.2 in AGC.  \nKeywords: Claudins; Gastric cancer; Targeted therapy; Biomarker  \nINTRODUCTION  \nGastric cancer (GC) is the fifth leading causes of cancer-related death worldwide [1,2] . For years, treatment for advanced GC (AGC) relied heavily on systemic chemotherapy, typically a fluoropyrimidine plus a platinum agent, with human epidermal growth factor receptor  \n2 (HER2)-targeted therapy (trastuzumab) being the major biomarker-driven option fora relatively small subset (~20%) of patients [1]. Based on the success of CheckMate-649, KEYNOTE-859 and RATIONALE-305, immune checkpoint inhibitor (ICI) combined with chemotherapy has been established as standard of care for treating patients with microsatellite instability-high, or HER2-negative and programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors [3-5]. Subsequently, ICI with chemotherapy plus trastuzumab was approved for HER2-positive and PD-L1 CPS ≥1 AGC [6,7] . Althoug","cbCaidxNKz6EUnsp","https://ap.wps.com/l/cbCaidxNKz6EUnsp","pdf",1230996,"English","# Introduction\n# Biological Role of CLDN18.2 in Normal Gastric Epithelium\n# Therapeutic Landscape of CLDN18.2 in Gastric Cancer\n# Author Contributions","[{\"question\":\"Why is CLDN18.2 considered a therapeutic target in advanced gastric cancer?\",\"answer\":\"CLDN18.2 is selectively expressed in normal gastric epithelium and is widely retained during tumorigenesis, becoming accessible on the tumor surface after cellular disruption, which supports targeted therapies such as monoclonal antibodies.\"},{\"question\":\"What evidence supports CLDN18.2 targeting with zolbetuximab?\",\"answer\":\"The SPOTLIGHT and GLOW phase III trials evaluated zolbetuximab with first-line chemotherapy in HER2-negative and CLDN18.2-positive advanced gastric cancer, showing improved clinical outcomes and manageable safety.\"},{\"question\":\"What other CLDN18.2-directed treatment strategies are discussed beyond zolbetuximab?\",\"answer\":\"The review highlights a pipeline including high-affinity anti-CLDN18.2 monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T-cell approaches evaluated in early-phase studies.\"}]","CLDN18.2 in Gastric Cancer - Current Therapeutic Landscape and Future Perspectives | PDF",1790114418,48]