Claudin-18.2 in Gastric and Gastroesophageal Junction Adenocarcinoma: From Biology to Therapeutic Targeting: A Narrative Review.

Gastric and gastroesophageal junction adenocarcinoma remains associated with a poor prognosis despite recent therapeutic advances. Claudin-18.2, a tight junction protein normally restricted to gastric epithelial cells, has emerged as a clinically validated and therapeutically actionable biomarker due to its preserved expression and aberrant membrane accessibility in malignant tissues. We conducted a narrative review of the literature (PubMed/MEDLINE and ClinicalTrials.gov; January 2000-December 2025) to summarize current knowledge on Claudin-18.2 biology, expression patterns, clinical relevance, and therapeutic targeting in gastric and gastroesophageal junction adenocarcinoma. Claudin-18.2 is frequently retained in gastric and gastroesophageal junction adenocarcinoma and can be reliably assessed using standardized immunohistochemistry. The phase III SPOTLIGHT and GLOW trials demonstrated that zolbetuximab significantly improves progression-free survival and overall survival when combined with first-line chemotherapy in Claudin-18.2-positive (moderate [2+] to strong [3+] membranous staining in ≥ 75% of tumor cells), human epidermal growth factor receptor 2-negative advanced disease. Emerging strategies, including antibody-drug conjugates, bispecific antibodies, and chimeric antigen-T-cell therapies, are under active investigation. Claudin-18.2 has established itself as a validated therapeutic target in gastric and gastroesophageal junction adenocarcinoma. Its integration into clinical practice reflects a shift toward biomarker-driven, multi-target treatment algorithms, although challenges remain regarding assay standardization, resistance mechanisms and optimal therapeutic sequencing alongside human epidermal growth factor receptor 2, microsatellite instability/deficient mismatch repair, and programmed death-ligand 1.