Aging and the extracellular matrix: A tumor-permissive microenvironment driving cancer progression

Aging is a significant cancer risk factor, yet its impact on the extracellular matrix (ECM) in tumor initiation and progression has been traditionally overlooked. While significant amounts of research focus on cellular and genetic links between aging and cancer, recent studies highlight how age-induced ECM changes create a tumor-permissive environment. Here we review this emerging research area, where age-related ECM alterations, such as age-induced increases in matrix stiffness, biochemical changes, and resultant dysregulated mechanosensitive pathways, are explored for their influence in cancer initiation and progression. Additionally, recent studies have showed how aged cells contribute to ECM alterations, further reinforcing tumor-permissive changes. This review examines both aspects of ECM aging, i.e. material-driven and cell-driven, and highlights current understandings of how ECM aging influences interactions within the tumor microenvironment in multiple cancer types, with a focus on biomechanical aspects. We also discuss emerging age-mimetic in vitro models facilitating studies of age-dependent cancer progression and therapeutic responses. Finally, we review therapeutic strategies that target aging-associated components or ECM changes to improve treatment efficacy.