Claudin 18.2: From a Tight Junction Protein to a Breakthrough Target in Solid Tumor Immunotherapy.

Abstract

Claudin 18.2 (CLDN18.2), a tight junction protein largely confined to normal gastric mucosa, is overexpressed and mislocalized on the surface of gastric, gastroesophageal, pancreatic, and other gastrointestinal cancers. This pattern has made CLDN18.2 a leading target in solid tumor immunotherapy. This review traces its path from a structural junctional component to a clinically relevant antigen and assesses the therapeutic platforms built around it. We discuss monoclonal antibodies, especially zolbetuximab, whose phase III SPOTLIGHT and GLOW trials improved survival in CLDN18.2-positive, HER2-negative gastric and gastroesophageal junction adenocarcinoma and led to regulatory approval. We then evaluate antibody-drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies, comparing their mechanisms, efficacy, toxicity, and resistance. We also examine the rationale for combining CLDN18.2-directed agents with immune checkpoint inhibitors, although clinical evidence for synergy remains indirect. Major challenges include antigen loss and heterogeneity, autophagy-mediated ADC resistance, on-target gastrointestinal toxicity, cytokine release syndrome, and unstandardized expression thresholds. Because optimal cutoffs differ by modality, patient selection should follow the intended therapeutic class rather than a universal biomarker score. Overall, CLDN18.2-directed therapy is a maturing precision oncology strategy; its impact will depend on randomized data, better biomarkers, and rational combinations.