Histology-defined activated cancer-associated fibroblasts are associated with poor survival in diffuse-type gastric...

Activated cancer-associated fibroblasts (aCAFs), characterized by distinct histological features including fibroblast proliferation and extensive desmoplasia, play a key role in tumor progression induced by cancer cell infiltration and may serve as important predictive and prognostic factors in gastric cancer (GC). This study investigated the relationship between aCAFs and clinicopathologic factors and their impact on survival outcomes in 691 GC patients across two independent cohorts. aCAFs were identified based on histological features on H&E-stained slides, and clinicopathological parameters, survival outcomes, immune cell composition, and transcriptomic features were comprehensively evaluated. Publicly available transcriptomic datasets were also analyzed for translational insights. aCAFs were significantly associated with advanced T and N stages, vascular/lymphatic/perineural invasion, and necrosis. Higher histological grade tended to correlate with increased aCAF frequency (P = 0.061). Notably, aCAFs were less frequently observed in diffuse-type GC according to Lauren classification and in poorly cohesive carcinoma according to WHO classification compared to other subtypes (all P < 0.05). The presence of aCAFs was significantly associated with poor survival in diffuse-subtype GC and WHO-defined poorly cohesive carcinoma on univariate and multivariate analyses (all P < 0.05). aCAFs correlated with immune dysfunction but were not related to CD4 + and CD8 + T cell counts. Incorporating aCAF status modestly but consistently improved survival prediction in machine learning-based prognostic models. Histologically identifiable aCAFs on routine H&E slides represent a clinically accessible prognostic biomarker in diffuse-subtype GC, highlighting the importance of stromal morphology in risk stratification and providing a translational framework for future therapeutic studies targeting the tumor microenvironment.