Senescent fibroblasts as drivers of malignant progression in gastric cancer.

Abstract

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and contribute substantially to gastric cancer progression. However, the phenotypic and functional heterogeneity of CAFs in gastric cancer remains incompletely characterized. Here, we analyzed single-cell transcriptomic data from gastric cancer samples and revealed a distinct CAF subset with cellular senescence-associated features. Pathway enrichment analysis demonstrated marked activation of hypoxia-related signaling in senescent CAFs, whereas pseudotime analysis suggested that these cells may arise from other CAF subtypes. By mimicking hypoxic conditions in vitro, we induced CAF senescence and employed co-culture models with gastric cancer cell lines (AGS, HGC27) to evaluate their effects. Mechanistically, hypoxia-induced mitochondrial dysfunction promoted CAF senescence. Functional assays further demonstrated that senescent CAFs promoted malignant phenotypes of gastric cancer cells in vitro and enhanced tumor growth in vivo. Collectively, these findings identify hypoxia as an important driver of CAF senescence and highlight senescent CAFs as potential therapeutic targets in gastric cancer.