Tissue porosity and nuclear deformation jointly determine subtotal and absolute limits of cell migration. Cell migration efficacy is a joint function of substrate porosity and nuclear deformability, with MMP activity and mechanocoupling as modulators. (A) Minor deformation of nuclei and optimal velocity during migration through tissue of sufficient to high porosity, with mononuclear shapes in ellipsoid and polymorphonuclear nuclei in partly unfolded state. (B) Significant deformation of the nucleus and migration delay in cells moving through dense ECM with pore cross sections much below the nondeformed nucleus size. Mononuclear nuclei are compressed in their entirety and adopt hourglass-like or cigar-like shapes, whereas polymorphonuclear deformation consists of unfolding with transient pearl chain–like configuration as maximum. Maximal deformation is reached when the nucleus deforms to ∼10% of its original cross section, reaching a subtotal migration limit. (C) Migration arrest during confrontation with pore cross sections that exhaust the deformation capability of the nucleus. Both mono- and polymorphonuclear nuclei of migration-arrested cells retain a roundish, collapsed morphology with nonproductive transient prolapse, the cross section of which matches the geometry of the pore (∼5–10% of the original nuclear cross section). Modulators of migration rates near the physical limit include (1) pericellular proteolysis by MMPs that widens pore cross sections and (2) mechano-coupling toward ECM determining the force with which the nucleus is transported. CS, cross section; CR, compression ratio (degree of nuclear deformation versus nondeformed state); Tu, tumor cells; T, T blast; PMN, polymorphonuclear neutrophil. White arrows, direction of migration.