Cancer-associated fibroblasts as a critical driver in tumor metastasis: The mechanisms and future perspectives.

Tumor metastasis represents a lethal event for patients due to the lack of effective treatments. Compared with primary tumors, the components of the tumor microenvironment (TME) of metastatic tumors are different. Tumor cells alone are unable to metastasize. Cancer-associated fibroblasts (CAFs), as one major component of TME, drive tumor metastasis. In metastatic lesions, the proportion of CAFs is significantly higher and is spatially close to tumor cells with high metastatic potential. CAFs themselves are resistant to chemoradiotherapy and have strong invasive ability based on their major role in degrading the extracellular matrix (ECM). Furthermore, CAFs determined the organs to which tumor cells metastasize. By interaction with tumor cells, CAFs were activated, transdifferentiated, and in turn enhanced the invasive ability of tumor cells. Tumor cells also promoted the infiltration of CAFs in tumor tissues, allowing them to establish a pre-metastatic microenvironment. In this review, we have deeply analyzed the association of CAFs and tumor metastasis from the perspectives of exosomes, metabolic reprogramming, suppression of anti-tumor immunity, and epigenetic modification. We also discussed the future perspectives of CAFs-based anti-metastasis strategies. This information may deepen our understanding of CAFs-initiated tumor metastasis and shed novel insight into the development of anti-metastasis therapies.