Mechanotransduction plays a crucial role in regulating many biological processes. Changes in tissue stiffness are associated with disease; for instance, tumoral cells with metastatic potential have been linked to cell softening. Natural killer (NK) cells are key players in the tumour response, but it is unknown whether they are influenced by tissue or cellular stiffness. Gel substrates can be used to study lymphocyte mechanosensitivity, although visualisation of the immune synapse on a 2D surface can be challenging. Here, Daniel Davis and colleagues (Friedman et al., 2021) develop a novel method to study the effect of target stiffness on NK cells by using cell-sized spherical alginate beads coated with different ligands as surrogate targets. Using this approach, the authors show that there is an enhanced NK cell activation owing to degranulation and secretion of different cytokines on stiffer substrates. Furthermore, combining the 3D alginate beads with advanced quantitative microscopy, they demonstrate that the target stiffness affects several steps of immune synapse function, including cell spreading, polarization of the microtubule-organising centre (MTOC) and distribution of lytic granules, with formation of unstable synapses and impaired NK cell function on soft targets. Taken together, these findings represent the first study of the role of mechanical forces in NK cell activation and point to disease-induced cell softening as a novel means of immune evasion.
