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

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.