Contributed Talk

Mechanosensing regulates immune killer cell-mediated immune surveillance

Archana K. Yanamandra^1,2, Xiangda Zhou¹, Jingnan Zhang², Galia Montalvo^1,3,4, Doreen Biedenweg⁵, Markus Hoth¹, Franziska Lautenschläger^3,4, Oliver Otto⁵, Aránzazu del Campo^2,6, Bin Qu¹

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Natural killer (NK) cells are essential in eliminating tumorigenic cells. Their ability to efficient locate and destroy target cells in complex three-dimensional (3D) environments is critical for their functions under physiological conditions. Recent studies suggest that NK cell activation is regulated by substrate stiffness, but the role of mechanosensing in regulating NK cell killing efficiency in physiologically relevant scenarios remains poorly understood. In our study, we found that the responsiveness of NK cells was influenced by the stiffness of tumor cells. NK cell killing efficiency in 3D was impaired against softened tumor cells, while it is enhanced against stiffened tumor cells. Furthermore, we found that the durations required for NK cell killing and detachment are significantly shortened for stiffened tumor cells. Additionally, we identified PIEZO1 as the predominantly mechanosensitive ion channel expressed in NK cells. We observed that perturbation of PIEZO1 abolished stiffness-dependent NK cell responsiveness, significantly impaired the killing efficiency of NK cells in 3D, and substantially reduced NK cell infiltration into 3D collagen matrices. Conversely, PIEZO1 activation enhances NK killing efficiency as well as infiltration. Our findings highlight the crucial role of PIEZO1-mediated mechanosensing in NK cell killing functions and how environmental physical cues influence NK cell functions under physiological conditions.