Spatially defined danger zone shapes gastric cancer progression through CCDC80+ fibroblast–induced CD8+ T cell dysfunction

Gastric cancer (GC) shows marked heterogeneity driven by the tumor microenvironment, leading to therapeutic resistance and poor prognosis. Using spatial transcriptomics of invasive murine tumors and human GC samples, we identified a distinct stromal–immune–vascular core region, termed the ‘danger zone’, which is enriched in diffuse-type GC and strongly linked to advanced stage and an immunosuppressive tumor microenvironment. Non-negative matrix factorization using danger zone signature genes stratified GC patients into two subtypes, with Subtype 2 exhibiting worse survival and impaired immunotherapy response. An XGBoost classifier based on 13 key genes—including CCDC80, MSRB3, FBLN1, and SPARCL1—accurately predicted subtypes and prognosis across cohorts. Single-cell and spatial analyses identified CCDC80 + fibroblasts as key drivers within the danger zone. Mechanistically, CCDC80 + fibroblasts recruit effector CD8 + T cells through CXCL12–CXCR4 signaling and induce their dysfunction by markedly upregulating PD-1 and TIM-3, thereby promoting exhaustion and apoptosis. The interactions were validated using fibroblast-CD8 + T cell co-cultures and CXCL12 blockade. Finally, a LightGBM model predicted danger zone scores directly from H&E slides, correlating with stromal infiltration and patient survival. This study defines the danger zone as a key spatial feature of GC progression and immunosuppression, offering novel biomarkers, prognostic tools, and therapeutic targets.