Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.

This review summarizes the current knowledge on cancer-associated fibroblasts (CAFs) and focuses on the recent discoveries of CAF molecular and functional heterogeneity in several malignancies. The discovery of CAF heterogeneity provides a potential explanation for previous seeming conflicting studies that targeted CAFs. Indeed, CAFs have been demonstrated to play multiple tumor-promoting roles, but also to potentially have tumor-restraining functions, which highlights the need to design subtype-specific therapies. The characterization of CAF heterogeneity will be pivotal for the development of effective combinatorial approaches for cancer treatment.