Provoking myofibroblast death: Strategies to resolve fibrosis and remodel tumor microenvironment

Fibrosis is marked by the excessive accumulation of extracellular matrix (ECM) components, leading to tissue scarring and progressive loss of organ function. Myofibroblasts, which emerge during tissue repair, are specialized contractile cells exhibiting features of both fibroblasts and smooth muscle cells. Their expression of α-smooth muscle actin facilitates contractile activity, while their persistent activation and overproduction of ECM components contribute significantly to pathological wound contraction and fibrotic progression. Beyond ECM production, myofibroblasts play a significant role in the tumor microenvironment (TME) of various solid tumors. The TME is a complex network of immune cells, blood vessels, ECM components, and stromal cells like fibroblasts and myofibroblasts that surrounds and interacts with cancer cells, thereby influencing tumor growth, progression, and therapy responsiveness. Through these interactions, myofibroblasts modulate inflammation, angiogenesis, and tissue remodeling. Maintaining myofibroblast homeostasis is therefore crucial, as its disruption can drive the onset of chronic fibrotic conditions and malignancies. This review explores preclinical and clinical developments in targeting myofibroblasts in fibrotic and TME across various disease models, including hypertrophic scar, idiopathic pulmonary fibrosis, oral submucous fibrosis, cardiac fibrosis, and the desmoplastic stroma of pancreatic and breast cancers.