Morpho-functional plasticity of tumour-associated macrophages: linking cell shape, ultrastructure, and immune regulation in cancer

Macrophages are highly adaptable immune cells that play dual roles in the tumor microenvironment (TME), either promoting or restraining tumor progression. Their polarization into M1 and M2 tumor-associated macrophage (TAM) phenotypes is classically defined by molecular and biochemical cues. Recent evidence shows that morphology also significantly influences the macrophage function and behavior. This review highlights the correlation between macrophage shape and function, and how cytoskeletal remodeling, extracellular matrix (ECM) stiffness, and topographical patterning regulate macrophage polarization under in vitro and in vivo conditions. We further discuss the ultrastructural features of distinct phenotypes and their mechanistic links to tumor growth and metastasis. Therapeutic strategies that target morphology through ECM modulation, engineered biomaterials, and nanoparticle platforms are examined alongside modern imaging and machine learning tools that enable precise morphometric analysis. Finally, we address the translational progress and limitations of current 2D versus 3D model systems. Overall, this review emphasizes macrophage morphology as a critical yet underexplored determinant of immune function and tumor dynamics.