Lipid droplets are rigid and physically suppress phagocytosis, unless cell compression or stretching activates actomyosin.

As with many cell types, macrophages are sometimes filled with micron-sized lipid droplets (LD's), but effects on phagocytosis of other cells, particulates, and microbes remain unclear. Here, we show that LDs restructure the cytoskeleton but remain round, consistent with a high interfacial tension; functionally, LD's impair actomyosin-driven uptake, which proves independent of target size. Engulfment of targets starts at the apical surface, but LD's displace apical actomyosin to the basal cortex. Partial rescue occurs tissue-relevant compressive stresses which activate actomyosin. Macrophages that are densely filled with LD's or pre-engulfed rigid beads likewise activate actomyosin, which again rescues phagocytosis relative to sparsely loaded cells. As further evidence of LD rigidity, both LD's and rigid beads impede macrophage migration through small pores, and LD's pressed into a nucleus cause rapid focal rupture independent of actin. LD rigidity thus disrupts cytoskeleton organization and nucleus integrity, suppressing motility processes unless actomyosin is activated by cell compression or stretching.