Review Highlights Epigenetic Reprogramming Over Genetic Mutations in Cancer-Associated Fibroblasts Function

Cancer-associated fibroblasts (CAFs) constitute a heterogeneous population of stromal cells whose tumor-modulating activities are highly context-dependent. Unlike cancer cells, CAFs rarely harbor stable genetic mutations; instead, their phenotypic plasticity is largely driven by reversible epigenetic reprogramming. Within the tumor microenvironment (TME), CAFs function as key regulators by secreting extracellular matrix (ECM) components, paracrine growth factors, cytokines, and metabolic intermediates that collectively promote tumor growth, invasion, and therapeutic resistance. Recent advances in cancer biology have shifted attention from solely cataloging coding-sequence mutations toward understanding the epigenetic mechanisms that shape CAF identity and function. Major epigenetic regulatory mechanisms include DNA methylation, histone modifications, and RNA modifications, which dynamically regulate chromatin structure and gene expression without altering the underlying DNA sequence. Emerging evidence indicates that the activation and functional heterogeneity of CAFs are predominantly governed by these epigenetic alterations rather than by permanent genetic changes. Epigenetic reprogramming enables CAFs to acquire diverse tumor-promoting properties, including remodeling of the extracellular matrix, modulation of intercellular signaling pathways, and secretion of cytokines that influence gene expression in neighboring cancer and immune cells. These processes ultimately contribute to tumor initiation, progression, metastasis, and resistance to therapy. This review summarizes recent advances in understanding how epigenetic modifications regulate CAF activation and function within the tumor microenvironment. In addition, we discuss the potential of targeting CAF-associated epigenetic pathways as a promising therapeutic strategy for cancer treatment.