Integrin-mediated mechanotransduction in the tumor microenvironment: macrophage-centered signaling mechanisms and...

Tumor-associated macrophages (TAMs) play a critical role in the immunosuppressive tumor microenvironment (TME). Although the biochemical signaling pathways regulating TAMs have been extensively elucidated, how these cells persistently sense physical properties of the tumor stroma-such as matrix stiffness, tension, and compression-and translate them into sustained immunosuppressive programs remains to be systematically addressed.

Unlike other infiltrating immune cell populations that primarily engage in transient adhesive interactions, TAMs utilize integrins for stable spatial anchoring and continuous mechanotransduction. In this review, we synthesize current evidence on the integrin-TAM mechanosensing axis. We first distinguish the persistent mechanobiological features of TAMs from those of structural stromal cells and other transiently infiltrating lymphocytes. Subsequently, we delineate how force-dependent signaling shapes TAM phenotypic plasticity, metabolic reprogramming, and spatial organization. Crucially, we define a self-amplifying biomechanical-immune feedback framework, demonstrating how mechanically remodeled TAMs actively exacerbate extracellular matrix stiffening to consolidate the immunosuppressive niche. Furthermore, we critically evaluate the translational relevance of this axis, analyzing the limitations of past single-target integrin inhibitors and highlighting the emerging potential of multidimensional combination therapeutic strategies.

Targeting integrin-dependent mechanotransduction provides a rational, system-level strategy to dismantle mechanically reinforced immune barriers. Breaking this interlocking feedback framework offers new insights for remodeling the TME and enhancing the efficacy of current immunotherapies.