Hijacked Immune Cells Traverse Microenvironmental Barriers by Positioning and Pushing their Intracellular Parasite Cargo

Cell migration is fundamental to development, homeostasis, and immunity, and requires cells to traverse space-limited microenvironments by deforming intracellular organelles such as the nucleus. Although nuclear mechanics are established as a rate-limiting factor during confined migration, how cells transport bulky foreign cargo remains unclear. Here, using Toxoplasma gondii , a disease-causing parasite that hijacks motile immune cells for dissemination while replicating into large intracellular assemblies, we discover that parasitic cargoes exceed the size and stiffness of host nuclei, and therefore constitute a primary bottleneck for migration. We uncover a mechanoadaptive response to parasite size, characterized by size-dependent intracellular repositioning, myosin-II contractility, and bleb-based protrusions. This reprogramming of forces and subcellular architecture enables the transport of oversized, mechanically rigid cargo through space-limited microenvironments. These findings establish a mechanobiological principle of how cells size-dependently adapt forces and their subcellular architecture to accommodate intracellular objects that challenge the physical limits of cell migration.