Cancer-Associated Fibroblasts in Gastrointestinal Cancer Metastasis: Mechanisms and Emerging Therapeutic Strategies

Metastasis is the primary cause of mortality across gastrointestinal (GI) cancers, including colorectal, gastric, pancreatic, biliary and esophageal cancers. Cancer-associated fibroblasts (CAFs) constitute the dominant stromal component of the desmoplastic GI tumor microenvironment (TME) and regulate every stage of metastatic progression. This review systematically summarizes CAF-mediated pro-metastatic mechanisms in GI tumors, including extracellular matrix (ECM) remodeling, paracrine oncogenic signaling, immune exclusion, angiogenesis, lymphangiogenesis, pre-metastatic niches (PMNs) construction and therapeutic resistance. Notably, CAFs are heterogeneous populations with context-dependent dual functions: certain myofibroblastic CAF (myCAF) subsets restrain tumor progression in pancreatic ductal adenocarcinoma (PDAC), while inflammatory CAFs (iCAFs) drive metastasis and immune suppression. Antigen-presenting CAFs (apCAFs) exert divergent immunomodulatory effects depending on tumor context. Rather than acting as uniformly tumor-promoting stromal cells, CAFs represent heterogeneous and plastic populations whose functions vary by tumor type, spatial niche, and metastatic stage. We further discuss why broad CAF depletion has shown limited clinical success and emphasize the need for subtype-specific, context- aware CAF-targeted strategies.