Cancer-associated fibroblasts: Orchestrators of the peritoneal metastatic microenvironment

Peritoneal metastasis (PM) represents a terminal stage of numerous abdominal malignancies, including gastric, colorectal, and ovarian cancers, and is associated with a dismal prognosis and limited therapeutic options. The peritoneal tumor microenvironment (TME) is a complex and dynamic ecosystem that actively governs cancer cell dissemination, implantation, and proliferation. Among the diverse cellular components of the TME, cancer-associated fibroblasts (CAFs) have emerged as principal regulators of this pro-tumorigenic niche. This review provides a comprehensive synthesis of current evidence regarding the multifaceted roles of CAFs in driving PM. The diverse origins of peritoneal CAFs were examined, with a particular focus on the pivotal process of mesothelial-to-mesenchymal transition (MMT), and the profound functional heterogeneity within the CAF population was explored. Moreover, the mechanisms through which CAFs promote metastasis were delineated, including the extensive remodeling of the extracellular matrix (ECM) that generates invasive pathways and modulates mechanotransduction. Furthermore, the complex CAF secretome, comprising cytokines, chemokines, growth factors, and extracellular vesicles that directly stimulate cancer cell motility, invasion, and survival, was investigated. Besides, the critical role of CAFs in modulating metabolic symbiosis, particularly through the provision of lipids that enhance cancer cell membrane fluidity and invasiveness, was also addressed. Finally, the mechanisms by which CAFs establish a profoundly immunosuppressive microenvironment by recruiting and polarizing myeloid cells, inhibiting T-cell function, and creating a physical barrier to immune surveillance were elucidated. In conclusion, CAFs are important regulators of the peritoneal metastatic cascade, coordinating a spectrum of pro-tumorigenic events that collectively facilitate tumor progression and therapeutic resistance.