Cancer-associated fibroblasts: multifaceted regulators of the tumor microenvironment and emerging therapeutic targets

Cancer-associated fibroblasts (CAFs) are a heterogeneous population of nonmalignant stromal cells that influence tumor progression and treatment response. They can arise from resident fibroblasts and other progenitor populations, with their relative contributions varying across tumor types and experimental settings. CAF states and functions are shaped by their cellular origins, local signals, spatial niches, and therapeutic pressure. CAFs participate in extracellular matrix remodeling, immune regulation, metabolic interactions, and angiogenesis, with effects that can promote or restrain tumor progression depending on tumor type and local conditions. This review summarizes CAF origins, molecular states, functional diversity, and signaling networks. We assess therapeutic strategies involving CAF depletion, extracellular matrix modification, signaling disruption, and phenotypic normalization, distinguishing preclinical findings from clinical outcomes. The clinical benefit of these approaches requires further validation in defined patient populations. Finally, we discuss how single-cell and spatial profiling and patient-derived models may improve CAF characterization and inform the development of selective stromal interventions.