PH of Microenvironment Directly Modulates the Phenotype and Function of Cancer-Associated Fibroblasts

Cancer-associated fibroblasts within the tumor microenvironment have been studied extensively, including their differential roles in promoting cancer growth and metastasis, promoting an immune suppressive microenvironment, and reshaping the stiffness of the extracellular matrix. Fibroblasts have diverse functions owing to their heterogeneous phenotypes shaped by the microenvironment. Increased acidity is a crucial feature of the tumor microenvironment, contributing to the generation of cancer-associated fibroblasts. Our data show that a low pH drives the formation of cancer-associated fibroblasts in vitro, while increasing pH activates the self-remodeling features of these cells by limiting their proliferation and downregulating the production of extracellular matrix-associated proteins. Our findings show that cancer-associated fibroblasts are a versatile population that can be reprogramed toward a quiescent phenotype with reduced acidity in the tumor microenvironment. pH regulation could be a potential strategy to target fibroblasts for cancer therapy.