Cancer-associated fibroblasts: origins, functional heterogeneity and therapeutic potential

Cancer-associated fibroblasts (CAFs) are integral components of the tumor microenvironment (TME) and are increasingly recognized as critical regulators of nearly every hallmark of cancer. Once viewed as a uniform, protumorigenic cell type, it is now clear that CAFs comprise a spectrum of dynamic and plastic functional states with both tumor-promoting and tumor-restraining capacities. This functional duality, conceptualized within the framework of cancer as a "wound that fails to heal", is dictated by their diverse cellular origins, the specific activation pathways engaged (such as TGF-β and PDGF), and the evolving cues from the TME. In this Review, we dissect the multifaceted roles of CAFs, from their promotion of cancer cell proliferation, invasion and angiogenesis through secreted factors and extensive extracellular matrix (ECM) remodeling, to their profound influence on the immune landscape. We detail how distinct CAF subsets, such as myofibroblastic (myCAFs) and inflammatory (iCAFs) CAFs, orchestrate an immunosuppressive niche and contribute to therapeutic resistance. We also explore the compelling evidence for tumor-suppressive CAF functions, which have catalyzed a paradigm shift in therapeutic strategies-moving away from indiscriminate CAF ablation towards nuanced approaches aimed at reprogramming their state. These strategies include modulating key signaling pathways, normalizing the CAF-remodeled ECM, and exploiting unique metabolic vulnerabilities. Finally, we discuss how advances in single-cell and spatial transcriptomics are resolving this complexity, paving the way for the development of precision therapies that can selectively neutralize pro-tumorigenic CAF activities while harnessing their beneficial functions to improve patient outcomes.