Remodeling the Stroma: The Role of ncRNAs in Cancer-Associated Fibroblasts and Therapeutic Implications for Digestive Tumors

The crosstalk between cancer-associated fibroblasts (CAFs) and tumor cells presents a formidable barrier to treating digestive malignancies, yet the molecular syntax governing this interaction is often overlooked. Recent studies have highlighted the indispensable function of non-coding RNAs (ncRNAs), which act not merely as bystanders but as architects of stromal remodeling. Here, we dissect how ncRNAs dictate the heterogeneity and function of CAFs, regulating fibroblast activation, metastatic niche formation, drug resistance, and metabolic reprogramming. We further examine how the exosomal transfer of ncRNAs reshapes the immune landscape, engineering a tumor-permissive microenvironment. Current clinical observations indicate, however, that indiscriminate depletion of CAFs is often counterproductive, underscoring the necessity of "stromal normalization." Targeting specific ncRNA master regulators to reprogram activated CAFs to a quiescent state-rather than destroying them-provides robust mechanistic support for the stromal normalization paradigm previously proposed.