Cancer-associated fibroblasts-derived exosomes in colorectal cancer progression: Mechanism and therapeutic opportunities.

Colorectal cancer (CRC) progression is profoundly shaped by the tumor microenvironment. Among stromal components, cancer-associated fibroblasts (CAFs) release small extracellular vesicles (exosomes) that deliver miRNAs, lncRNAs, circRNAs, proteins, and metabolites to malignant and immune cells. In CRC, CAF-derived exosomes (CAF-Exo) drive epithelial-mesenchymal transition, sustain stemness, stimulate angiogenesis, suppress antitumor immunity, and promote resistance to fluoropyrimidines and oxaliplatin. Representative mechanisms include exosomal miR-92a-3p activation of Wnt/β-catenin signaling, the lncRNA WEE2-AS1-mediated suppression of Hippo restraint with YAP activation, and circRNA cargos that reprogram autophagy or endothelial dynamics. Circulating CAF-Exo signatures are emerging as minimally invasive biomarkers for diagnosis, prognosis, and therapy stratification. However, translation remains limited by CAF heterogeneity, cargo variability, and incomplete in vivo characterization of vesicle dynamics. Therapeutic opportunities include blockade of exosome biogenesis or uptake, pharmacologic reprogramming of CAFs, and engineering vesicles to deliver targeted inhibitors or RNA-based therapeutics. This review synthesizes current mechanistic insights, evaluates biomarker potential, and outlines clinical priorities for targeting CAF-exosomal pathways in CRC.