Targeting claudins in gastric cancer: A novel GLOWing strategy in the SPOTLIGHT

Gastric cancer is one of the most aggressive and lethal malignancies, with limited reliable biomarkers to inform prognosis and therapeutic decision-making. Claudins, which are tight junction proteins that establish epithelial polarity, have recently emerged as clinically actionable targets. CLDN18.2, typically sequestered within the tight junctions of gastric epithelial cells, becomes accessible during malignant transformation and is currently regarded as a critical standard marker in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. Zolbetuximab, a chimeric IgG1 monoclonal antibody targeting CLDN18.2, has shown a survival advantage when used in conjunction with chemotherapy in phase III trials. In light of this evidence, novel strategies are being investigated, including antibody-drug conjugates (ADC) targeting CLDN18.2, bispecific antibodies (BsAb), and cell therapies such as (CAR-T). In parallel, the oncofetal antigen CLDN6, which is inactive in adult tissues but re-expressed in a subset of tumours, has emerged as an interesting target for the development of new therapeutic strategies under investigation. However, despite the development of new drugs and the approval of zolbetuximab, there are significant challenges to be addressed, such as intratumoural heterogeneity, sampling bias, and the absence of assay standardization with thresholds suitable for the modality. This review synthesizes the biology and clinical significance of claudins-particularly CLDN18.2 and CLDN6-, highlighting their potential as biomarkers for guiding precision medicine and future development of novel therapeutic agents in gastric cancer patients.