Mechanoresponsive reprogramming of tumor-associated macrophages during cancer progression

Abstract

Tumor-associated macrophages (TAMs) are critical regulators of the tumor microenvironment. They exhibit diverse pro-tumorigenic and antitumor phenotypes depending on their monocyte-derived or tissue-resident origins. Beyond biochemical signaling, the mechanical properties of the tumor microenvironment, including extracellular matrix stiffness, density, architecture, and spatial heterogeneity, can regulate TAM behavior. This review discusses how these mechanical cues influence TAM infiltration, polarization, and tumor-supportive functions. We further highlight how spatially distinct mechanical environments contribute to TAM heterogeneity within solid tumors. Furthermore, we evaluate how advanced 3D biomimetic cancer platforms, including hydrogels, spheroids, organoids, and microfluidic organ-on-a-chip models, have become essential for accurately recapitulating these mechanoresponsive behaviors and phenotypic adaptations in vitro. We also discuss the capacity and current limitations of these models in reproducing the mechanical properties of the tumor microenvironment. Finally, we discuss how understanding these mechanical regulatory pathways may reveal promising avenues for TAM-targeted therapeutic strategies, particularly those aimed at disrupting mechanical niches to achieve effective TAM depletion or antitumor reprogramming. We highlight the need to integrate TAM-targeted strategies with mechanobiological regulation. Collectively, these insights underscore the importance of mechanobiology in regulating macrophage plasticity and its therapeutic potential in clinical oncology.