CLDN18.2 and Gastric Cancer: Cancer Letters | July 2026

Introduction:

The treatment of advanced gastric cancer is rapidly evolving from conventional chemotherapy to biomarker-driven precision medicine. Claudin 18.2 (CLDN18.2), a tight junction protein selectively expressed in gastric epithelial cells and many gastric cancers, has emerged as one of the most promising therapeutic targets.

Why was this review needed?

Following the approval of zolbetuximab for HER2-negative, CLDN18.2-positive advanced gastric cancer, numerous CLDN18.2-targeted therapies are under development. This review summarizes the current evidence and future directions of this rapidly expanding therapeutic field.

What did the review show?

• CLDN18.2 is an established biomarker and therapeutic target in advanced gastric cancer.
• Zolbetuximab combined with chemotherapy is now the first approved CLDN18.2-targeted therapy for HER2-negative, CLDN18.2-positive gastric adenocarcinoma.
• Next-generation monoclonal antibodies are being developed to improve efficacy and durability of response.
• Antibody-drug conjugates (ADCs) enable selective delivery of cytotoxic agents to CLDN18.2-expressing tumor cells.
• Bispecific antibodies simultaneously target CLDN18.2 and immune pathways, enhancing antitumor activity.
• CLDN18.2-directed CAR-T cell therapy has shown encouraging early clinical activity in heavily pretreated patients.
• Combination strategies with chemotherapy, immunotherapy, and other targeted agents may further improve clinical outcomes.
• Resistance mechanisms, patient selection, biomarker standardization, and treatment-related toxicities remain important challenges.

Clinical Impact:

Routine assessment of CLDN18.2 expression is becoming increasingly important in advanced gastric cancer. Expanding CLDN18.2-directed therapies are expected to broaden personalized treatment options and improve outcomes for appropriately selected patients.

Take-Home Message:

CLDN18.2 has emerged as a major therapeutic target in gastric cancer, marking a shift toward biomarker-guided treatment. As monoclonal antibodies, ADCs, bispecific antibodies, and CAR-T therapies continue to evolve, precision targeting of CLDN18.2 is poised to become a cornerstone of future gastric cancer management.