Deciphering mechanical cues in the microenvironment: from non-malignant settings to tumor progression

The tumor microenvironment functions as a dynamic and intricate ecosystem, comprising a diverse array of cellular and non-cellular components that precisely orchestrate pivotal tumor behaviors, including invasion, metastasis, and drug resistance. While unraveling the intricate interplay between the tumor microenvironment and tumor behaviors represents a tremendous challenge, recent research illuminates a crucial biological phenomenon known as cellular mechanotransduction. Within the microenvironment, mechanical cues like tensile stress, shear stress, and stiffness play a pivotal role by activating mechanosensitive effectors such as PIEZO proteins, integrins, and Yes-associated protein. This activation initiates cascades of intrinsic signaling pathways, effectively linking the physical properties of tissues to their physiological and pathophysiological processes like morphogenesis, regeneration, and immunity. This mechanistic insight offers a novel perspective on how the mechanical cues within the tumor microenvironment impact tumor behaviors. While the intricacies of the mechanical tumor microenvironment are yet to be fully elucidated, it exhibits distinct physical attributes from non-malignant tissues, including elevated solid stresses, interstitial hypertension, augmented matrix stiffness, and enhanced viscoelasticity. These traits exert notable influences on tumor progression and treatment responses, enriching our comprehension of the multifaceted nature of the microenvironment. Through this innovative review, we aim to provide a new lens to decipher the mechanical attributes within the tumor microenvironment from non-malignant contexts, broadening our knowledge on how these factors promote or inhibit tumor behaviors, and thus offering valuable insights to identify potential targets for anti-tumor strategies.