Dynamic regulation of CLDN18.2 expression during immunotherapy: Implications for biomarker-driven therapy in gastric cancer.

430 Background: Claudin 18.2 (CLDN18.2) has emerged as a promising therapeutic target in gastric cancer (GC), yet its biological role in the tumor microenvironment (TME) and expression dynamics during treatment remain poorly understood. Methods: We assessed paired biopsies from patients with advanced GC undergoing anti–PD-1–based therapy. CLDN18.2 expression was evaluated by immunohistochemistry (IHC), and associations with PD-L1 and HER2 were examined. Multi-omics profiling, including digital spatial profiling and bulk RNA sequencing, characterized TME features linked to CLDN18.2 expression. Results: Among 201 patients, 84 (41.6%) had CLDN18.2-positive tumors. Of these, 65 (32.2%) were also PD-L1–positive, and 16(8%) co-expressed CLDN18.2, PD-L1, and HER2. CLDN18.2-positive tumors showed enrichment of cancer stem cell markers and stromal remodeling pathways, with concordant up-regulation of CD44 and MMP7 signaling. Notably, in HER2-negative, PD-L1–positive tumors, CLDN18.2 expression increased during anti–PD-1 therapy, indicating dynamic modulation under immune pressure. Conclusions: CLDN18.2 expression in GC is dynamic and can be up-regulated during anti–PD-1 therapy, particularly in HER2-negative, PD-L1–positive tumors. Longitudinal monitoring of CLDN18.2 may enable timely integration of CLDN18.2-targeted agents, supporting adaptive, biomarker-driven strategies to improve outcomes for patients with advanced GC.