Decoding the mechanical language of the tumor microenvironment: From physical forces to malignant behaviors.

Abstract

Malignant metastasis, the leading cause of cancer mortality, is initiated by tumor invasion, a process intrinsically linked to dynamic biomechanical alterations within the tumor microenvironment (TME). While recent reviews have established the role of extracellular matrix (ECM) stiffness, this review offers a distinct synthesis by focusing on the synergistic interplay between two critical, yet underappreciated, mechanical forces: solid stress and fluid pressure. We propose that these forces form an integrated mechanical barrier that actively promotes malignancy. As tumors grow, ECM deposition and spatial confinement generate substantial solid stress, while vascular dysfunction elevates fluid stress. This review uniquely details how this solid-fluid stress nexus drives malignant progression, immune suppression, and therapeutic resistance through coordinated mechanobiological signaling. We comprehensively synthesize how these altered forces regulate tumor cell behavior by focusing on mechanotransduction-the conversion of mechanical cues into biochemical signals. Finally, we outline a framework for novel therapeutic strategies that target this "physical barrier", with the goal of improving drug delivery, overcoming resistance, and advancing cancer treatment.