CDH6-high gastric cancers as exhibitors of a reproducible vascular–stromal, immune-excluded tumor microenvironment.

e15179 Background: Cadherin-6 (CDH6) is a developmental adhesion molecule aberrantly expressed in subsets of gastric cancer and associated with invasive behavior. While CDH6-high tumors have been hypothesized to exhibit immunosuppressive tumor microenvironment (TME) features, the extent to which CDH6 expression reflects coordinated vascular, stromal, and immune organization across cohorts has not been systematically evaluated. Methods: We conducted a multi-cohort analysis of gastric cancer RNA-sequencing datasets. Within each cohort, tumors were stratified into CDH6-high and CDH6-low groups using cohort-specific median transcripts per million (TPM). Immune and stromal cell-type enrichment was inferred using the xCell deconvolution algorithm. Associations with angiogenic signaling were explored through transcriptomic correlation with vascular endothelial growth factor (VEGF) family members. Results: Across ten independent cohorts, comprising 1,811 clinically annotated samples, CDH6-high tumors demonstrated a reproducible vascular–stromal–enriched tumor microenvironment. Endothelial cells were increased in 10/10 cohorts (p < 0.05), accompanied by enrichment of hematopoietic stem cells (9/10), pericytes (5/10), and elevated stromal scores (5/10), with concomitant epithelial depletion (5/10). Immune profiling showed consistent directional immune exclusion, including reduced γδ T cells (9/10), Th1 (6/10), Th2 (7/10), NK cells (5/10), CD8⁺ T-cell subsets (2–4/10), and reduced immune scores (0/10), with greater consistency in vascular and stromal features than immune effect sizes. Angiogenic signaling patterns were concordant with this phenotype, with VEGFB- and VEGFC-associated tumors showing endothelial expansion and increased stromal and microenvironment scores (9–10/10 cohorts), in contrast to VEGFA-associated stromal depletion and epithelial predominance. Conclusions: CDH6-high gastric cancers are associated with a reproducible, structurally organized vascular–stromal tumor microenvironment characterized by immune exclusion rather than immune absence. These findings support CDH6 expression as a marker of tumor microenvironmental architecture and highlight the relevance of angiogenic context for therapeutic stratification.