Principal mechanisms of extracellular matrix-mediated cell-cell communication in physiological and tumor microenvironments.

Cell-cell communication is essential for the regulated exchange of information between cells, coordinating critical cellular processes under physiological and pathological conditions. The extracellular matrix (ECM) is a complex three-dimensional (3D) intercellular macromolecular network that provides structural support to tissues, while actively modulating cellular functions and responses. ECM-mediated intercellular communication is a key player in both homeostasis and disease development. Particularly in cancer, ECM reorganization drives tumor development and progression, shaping dynamic interactions within the tumor microenvironment (TME). In this review, we present and discuss two principal mechanisms of matrix-mediated cell-cell communication in both physiological and cancerous contexts. First, we explore the impact of ECM biomechanical properties in mechanical sensing and communication, which govern key aspects of cell signaling, adhesion, and migration across normal and malignant tissues. Second, we discuss the role of the ECM in facilitating cell-cell communication through the controlled release and navigation of extracellular vesicles (EVs). EVs carry, among other constituents, proteins, enzymes, microRNAs (miRNAs), and signaling molecules that relay information to nearby or distant cells, modulating the initiation of metastasis and pre-metastatic niche formation. Conclusively, in this review, we highlight the critical role of targeting ECM dynamics in cell-cell communication under physiological processes and during cancer progression. Targeted therapies that modulate ECM components and interactions with cells hold promise for future treatment approaches.