Multi-omics reveals tumor microenvironment heterogeneity and therapeutic vulnerabilities in peritoneal metastasis of gastric cancer.

Peritoneal metastasis of gastric cancer (PMGC) is associated with a poor prognosis, with approximately one-third of patients presenting with peritoneal metastasis at diagnosis. Current systemic therapies have limited efficacy, underscoring the need for precise therapeutic targets in PMGC. We employed single-cell RNA sequencing (scRNA-seq) to characterize the cellular composition of the PMGC microenvironment, reconstruct epithelial cell developmental trajectories, and analyze intercellular communication networks. Spatial transcriptomics and multiplex immunohistochemistry were integrated to validate targets, and in vivo mouse models were used to assess therapeutic efficacy. Single-cell analysis identified a peritoneal metastasis (PM) signature associated with cancer cell differentiation origin and poor outcomes. We classified cancer cells as PM-high or PM-low based on this signature, with the PM-high group enriched in multiple oncogenic pathways and the PM-low group overexpressing CLDN18. Intercellular communication analyses showed epithelial cells and diverse subsets interact with regulatory T, natural killer, and proliferative T cells via PVR-TIGIT and NECTIN2-TIGIT. In vivo studies indicated that dual targeting of TIGIT and Claudin 18.2 (CLDN18.2) inhibited PMGC progression and ascites formation. These findings indicate that CLDN18.2 and TIGIT are potential therapeutic targets, whose combined inhibition suppresses PMGC progression and ascites formation, providing valuable insights for PMGC treatment.