Claudin-18.2: Molecular mechanisms to clinical translation in solid tumors (Review)

Abstract

Claudin 18.2 (CLDN18.2) is a functional subtype generated by alternative splicing of the CLDN18 gene. It is aberrantly overexpressed in a variety of gastrointestinal solid tumors such as gastric cancer and pancreatic cancer, and has emerged as a promising target for tumor targeted therapy. To date, zolbetuximab, a monoclonal antibody targeting CLDN18.2, has demonstrated survival benefits in phase III clinical trials. Antibody-drug conjugates, bispecific antibodies and chimeric antigen receptor T cell therapies also exhibit favorable application potential. Nevertheless, multiple challenges remain in this field. Distinction between CLDN18.1 and CLDN18.2 subtypes is often ambiguous, and the lack of unified immunohistochemistry testing criteria, including antibody selection and specimen types, leads to conflicting findings on prognostic research. Additionally, intratumoral heterogeneity, differential functions across tumor types and tumor microenvironment limitations further compromise the efficacy of targeted therapy. As a narrative review, this article systematically elaborates the molecular structure, expression regulatory mechanisms and clinicopathological value of CLDN18.2. Based on the data of 58 global clinical trials, it analyzes the current status, existing problems in testing standardization and drug development. Future directions are proposed, including standardizing detection protocols, developing differentiated drugs, optimizing combination regimens and overcoming drug resistance, aiming to provide references for the clinical translation and standardized application of CLDN18.2-targeted therapies.