From biting to engulfment: Target mechanics determines modes of phagocytosis through curvature--actin coupling

Abstract

Phagocytosis is a core innate immune process that clears targets spanning a wide range of mechanical properties, yet the role of target mechanics in recognition and engulfment remains unclear. Here, we combine theoretical modeling and experiments to reveal how target stiffness governs distinct modes of phagocyte-target interaction. We develop a membrane-based simulation framework in which both the engulfing cell and its target are deformable and undergo large shape changes, while actin-driven protrusions are regulated by curvature-sensitive membrane complexes. The model predicts three mechanical regimes with increasing target stiffness: (i) biting (trogocytosis), where part of the target is extracted; (ii) pushing, where the target is displaced rather than engulfed; and (iii) complete engulfment. We validate these predictions in epithelial clearance of apoptotic targets in vivo and macrophage engulfment of Giant Unilamellar Vesicles (GUVs) and lymphoma cells. Together, our results identify target mechanics as a key regulator of clearance and cell-cell interactions. Significance statementPhagocytosis is essential for immune defence, yet the physical principles governing engulfment of deformable targets remain poorly understood. Most theoretical models assume rigid particles, appropriate for phagocytosis of bacteria or fungi. When phagocytes engage dying cells or antibody-opsonised cancer cells, these targets undergo substantial shape changes during phagocytosis. We develop a theoretical model to simulate cell-cell interactions, enabling a mechanistic exploration of phagocytosis of soft targets. We utilize a model in which cytoskeletal protrusive activity is guided by curvature-sensitive membrane complexes, and show that target membrane rigidity dictates whether targets are fully engulfed, pushed away, or partially bitten. These mechanically driven dynamic regimes are validated experimentally using artificial elastic beads, GUVs, and lymphoma cells, both in vivo and in vitro.