Emerging evidence of targeting non-oncogenic drivers for gastric cancer: Claudin18.2 and beyond.

Human epidermal growth factor receptor 2 was the first successful molecular target in treating gastric cancer, marking a significant milestone for targeted therapies. Emerging evidence on Claudin18.2 (CLDN18.2) has recently reshaped the paradigm of therapeutic targets, expanding the focus beyond conventional oncogenic drivers. Therapeutic strategies now target tumor-associated molecules which highly expressed in tumors but are not necessarily critical for tumor growth or survival. Molecules such as trophoblast cell surface antigen 2, Caprin-1, and Nectin-4 are promising non-oncogenic targets for advanced gastric cancer treatment. Innovative therapeutic approaches, such as antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy, have accelerated the potential of targeting tissue-associated antigens. This review provides an update on CLDN18.2-directed therapies and explores the development of novel therapeutic strategies targeting non-oncogenic drivers. In addition, we discuss ongoing challenges, including biomarker overlap, resistance mechanisms, and future directions for next-generation molecular targeted therapy in gastric cancer.