Zolbetuximab: research progress and prospects in the treatment of gastric and gastroesophageal junction cancer targeting claudin 18.2

Gastric cancer (GC) and esophagogastric junction cancer (EGJC) impose a severe global burden, with traditional treatments plagued by poor efficacy, high toxicity, and chemoresistance. Claudin 18.2 (CLDN18.2), a highly tissue-specific target, is abnormally overexpressed in GC/EGJC with limited overlap with HER2 positivity or PD-L1 CPS ≥5, making it ideal for precision therapy. Zolbetuximab, a CLDN18.2-targeted ADC, exerts anti-tumor effects via "targeted binding-endocytosis-MMAE release", reducing systemic toxicity versus traditional chemotherapy. Pivotal trials (MONO, FAST, SPOTLIGHT/GLOW, ILUSTRO) confirmed its monotherapy efficacy and superior PFS/OS when combined with chemotherapy (EOX, mFOLFOX6, CAPOX) in CLDN18.2-positive (≥70% staining), HER2-negative advanced GC/EGJC patients, with manageable safety. SPOTLIGHT/GLOW laid the foundation for its first-line approval. Post-approval, it may expand to other CLDN18.2-positive tumors and neoadjuvant/adjuvant therapy, with combination regimen optimization. However, MMAE's long-term cumulative toxicity, uncertain safety in special populations, and rare severe adverse reactions require real-world validation. This review systematically summarizes zolbetuximab's research progress, providing a reference for clinical application and future studies.