Gastrointestinal cancers, including gastric, gastroesophageal junction, pancreatic, and biliary tract cancers, remain associated with poor outcomes due to late diagnosis and limited effective treatment options. Claudin-18.2 (CLDN18.2), a tight junction protein primarily found in the gastric epithelium and ectopically expressed in gastrointestinal tumors, has emerged as a promising therapeutic target across these diseases. This narrative review expands on existing discussions surrounding CLDN18.2-directed therapy in gastric and gastroesophageal cancer and provides a comprehensive, updated analysis of the rapidly evolving therapeutic landscape across multiple gastrointestinal malignancies, including pancreatic and biliary tract cancers. We summarize key developments following the approval of the monoclonal antibody zolbetuximab and critically evaluate emerging modalities, including bispecific antibodies, antibody–drug conjugates, and chimeric antigen receptor T-cell therapies, highlighting differences in mechanisms of action, efficacy, toxicity profiles, and mitigation strategies. We also discuss the clinical relevance of CLDN18.2 and PD-L1 co-expression, the rationale for pairing CLDN18.2-targeted therapy with immune checkpoint inhibitors, and early data supporting combination approaches. Additionally, we examine tumor heterogeneity, biomarker challenges, and emerging resistance mechanisms, alongside strategies to overcome them. Finally, we identify current limitations in the field, including inconsistent CLDN18.2 testing criteria, and outline prioritized future directions to optimize integration of CLDN18.2-directed therapies across gastrointestinal cancers. By looking beyond zolbetuximab and incorporating cross-platform comparison, immuno-oncology considerations, and multi-tumor context, this review provides a broad and forward-looking framework to guide clinical application and next-generation research in CLDN18.2-targeted therapy.
胃肠道癌症，包括胃癌、胃食管结合部癌、胰腺癌和胆道癌，由于诊断较晚且有效治疗手段有限，预后仍然不佳。Claudin-18.2（CLDN18.2）是一种主要表达于胃上皮细胞并在胃肠道肿瘤中异位表达的紧密连接蛋白，已成为这些疾病中颇具前景的治疗靶点。本文在现有关于CLDN18.2靶向治疗在胃癌和胃食管结合部癌中讨论的基础上，进一步对包括胰腺癌和胆道癌在内的多种胃肠道恶性肿瘤中快速发展的治疗格局进行了全面且最新的分析。我们总结了单克隆抗体佐贝妥昔单抗获批后的关键进展，并批判性评估了新兴治疗模式，包括双特异性抗体、抗体偶联药物和嵌合抗原受体T细胞疗法，重点分析了它们在作用机制、疗效、毒性特征及缓解策略方面的差异。同时，我们探讨了CLDN18.2与PD-L1共表达的临床意义、CLDN18.2靶向治疗与免疫检查点抑制剂联合应用的原理，以及支持联合方案的早期数据。此外，我们还分析了肿瘤异质性、生物标志物检测面临的挑战及新兴耐药机制，并探讨了相应的应对策略。最后，我们指出了该领域当前的局限性，包括CLDN18.2检测标准不统一等问题，并提出了优化CLDN18.2靶向治疗在胃肠道癌症中整合应用的未来重点方向。通过超越佐贝妥昔单抗的单一视角，结合跨平台比较、免疫肿瘤学考量及多瘤种背景，本综述为CLDN18.2靶向治疗的临床应用和下一代研究提供了一个广阔且前瞻性的指导框架。
肿瘤(癌症)患者之家