Abstract / Summary
Abstract Gastric cancer (GC) progression is driven not only by malignant epithelial cells but also by the surrounding stromal microenvironment, in which cancer-associated fibroblasts (CAFs) contribute to angiogenesis and immune evasion. However, the specific CAF states and the intercellular signaling through which they remodel this microenvironment remain incompletely characterized. Here, we integrated single-cell and spatial transcriptomics of an in-house GC cohort with public bulk, immunotherapy, and pan-cancer datasets, together with functional assays, to dissect CAF heterogeneity and its role in GC. Among nine fibroblast subpopulations, we identified an MMP1⁺ CAF subset that was enriched in tumor tissue, accumulated with tumor stage, and was associated with poor prognosis. MMP1⁺ CAFs occupied the initiation point of the fibroblast pseudotime trajectory and exhibited a stem-like phenotype enriched in extracellular matrix remodeling, epithelial–mesenchymal transition, and angiogenesis programs. Mechanistically, MMP1⁺ CAFs signaled to immature vascular endothelial cells through the GDF15–TGFBR2 axis, activating angiogenic pathways and the downstream transcription factor TCF12 to promote neovascularization; this effect was abrogated in vitro by the GDF15 inhibitor Ponsegromab. In parallel, MMP1⁺ CAFs engaged tumor cells to upregulate VEGFA, which in turn acted on endothelial cells via VEGFR1/VEGFR2. Beyond angiogenesis, MMP1⁺ CAFs interacted with FOLR2⁺ M2-like macrophages to establish an immunosuppressive microenvironment and to predict resistance to immunotherapy. Finally, pan-cancer analysis revealed the broad conservation of MMP1⁺ CAFs and their generally adverse prognostic association across colorectal, lung, hepatocellular, and pancreatic cancers. Together, these findings define MMP1⁺ CAFs as a stromal state coordinating angiogenesis in gastric cancer and highlight the GDF15–TGFBR2 axis as a candidate therapeutic target.