Cell Softness Prevents Cytolytic T-cell Killing of Tumor-Repopulating Cells

Abstract Biomechanics is a fundamental feature of cell. However, the manner by which actomysin tension affects tumor immune evasion remains unclear. Here we show that although cytotoxic T lymphocytes (CTL) can effectively destroy stiff differentiated cells, they fail to kill soft tumor-repopulating cells (TRC). TRC softness prevented membrane pore formation caused CTL-released perforin. Perforin interacting with nonmuscle myosin heavy-chain 9 transmitted forces less F-actins in TRC, thus generating an inadequate contractile force for perforin formation. Stiffening allowed ability drill through membrane, leading CTL-mediated killing TRC. Importantly, overcoming mechanical human also enhanced cell death CTL, potentiating mechanics-based immunotherapeutic strategy. These findings reveal mechanics-mediated evasion, potentially providing alternative approach immunotherapy. Significance: Tumor-repopulating evade CD8+ cytolytic T-cell mechanism, underlying impediment at synapse site.