Immune cells adapt to confined environments in vivo to optimise nuclear plasticity for migration.

Cells navigating in complex 3D microenvironments frequently encounter narrow spaces that physically challenge migration. While in vitro studies identified nuclear stiffness as a key rate-limiting factor governing the movement of many cell types through artificial constraints, how cells migrating in vivo respond dynamically to confinement imposed by local tissue architecture, and whether these encounters trigger molecular adaptations, is unclear. Here, we establish an innovative in vivo model for mechanistic analysis of nuclear plasticity as Drosophila immune cells transition into increasingly confined microenvironments. Integrating live in vivo imaging with molecular genetic analyses, we demonstrate how rapid molecular adaptation upon environmental confinement (including fine-tuning of the nuclear lamina) primes leukocytes for enhanced nuclear deformation while curbing damage (including rupture and micronucleation), ultimately accelerating movement through complex tissues. We find nuclear dynamics in vivo are further impacted by large organelles (phagosomes) and the plasticity of neighbouring cells, which themselves deform during leukocyte passage. The biomechanics of cell migration in vivo are thus shaped both by factors intrinsic to individual immune cells and the malleability of the surrounding microenvironment.