The extracellular matrix of solid tumours is often stiffer than that of most healthy tissues and this can impair T cell migration and antitumour responses. A new study in Cell shows that CD8+ T cells subjected to the biomechanical stress of ‘stiff’ tumours upregulate the transcription factor OSR2 that suppresses T cell cytotoxic function and drives exhaustion.

Using an in vitro system comprising hydrogels of varying stiffness to mimic the tumour extracellular matrix and anti-CD3 plus anti-CD28 to activate T cells, the authors showed that CD8+ T cells activated in the context of high matrix stiffness predominantly develop an exhausted phenotype (PD1+TIM3+) rather than a cytotoxic phenotype (IFNγ+TNF+).