Targeting the devil: Strategies against cancer-associated fibroblasts in colorectal cancer

Cancer-associated fibroblasts (CAFs), as significant constituents of the tumor microenvironment (TME), play a pivotal role in the progression of cancers, including colorectal cancer (CRC). In this comprehensive review, we presented the origins and activation mechanisms of CAFs in CRC, elaborating on how CAFs drive tumor progression through their interactions with CRC cells, immune cells, vascular endothelial cells, and the extracellular matrix within the TME. We systematically outline the intricate web of interactions among CAFs, tumor cells, and other TME components, and based on this complex interplay, we summarize various therapeutic strategies designed to target CAFs in CRC. It is also essential to recognize that CAFs represent a highly heterogeneous group, encompassing various subtypes such as myofibroblastic CAF (myCAF), inflammatory CAF (iCAF), antigenpresenting CAF (apCAF), vessel-associated CAF (vCAF). Herein, we provide a summary of studies investigating the heterogeneity of CAFs in CRC and the characteristic expression patterns of each subtype. While the majority of CAFs contribute to the exacerbation of CRC malignancy, recent findings have revealed specific subtypes that exert inhibitory effects on CRC progression. Nevertheless, the comprehensive landscape of CAF heterogeneity still awaits exploration. We also highlight pivotal unanswered questions that need to be addressed before CAFs can be recognized as feasible targets for cancer treatment. In conclusion, the aim of our review is to elucidate the significance and challenges of advancing in-depth research on CAFs, while outlining the pathway to uncover the complex roles of CAFs in CRC and underscore their significant potential as therapeutic targets.