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

Biomechanics is a fundamental feature of a cell. The manner by which a mechanical feature could affect immune evasion of tumor cells remains an enigma. Here we show that although cytotoxic T lymphocytes (CTL) can effectively destroy stiff differentiated tumor cells, they fail to kill tumor-repopulating cells (TRC), whose softness effectively impedes the pore formation process through perforin released from CTLs. Mechanistically, perforin interacting with nonmuscle myosin heavy chain 9 transmits forces to fewer F-actins in soft TRCs, thus inducing a weak contractile force which is inadquate for pore formation by perforin. Stiffening soft TRCs confers perforin the drilling ability, leading to CTLs killing the TRCs, thus achieving a better tumor immunotherapeutic outcome. More importantly, overcoming the mechanical softness also enhances the killing of human TRCs by human CTLs. These findings provide mechanics-based immunotherapeutic strategies with potential clinical applications.