Cytotoxic lymphocytes target characteristic biophysical vulnerabilities in cancer

Immune cells identify and destroy tumors by recognizing cellular traits indicative of oncogenic transformation. In this study, we found that myocardin-related transcription factors (MRTFs), which promote migration and metastatic invasion, also sensitize cancer cells to the immune system. Melanoma and breast cancer cells with high MRTF expression were selectively eliminated by cytotoxic lymphocytes in mouse models of metastasis. This immunosurveillance phenotype was further enhanced by treatment with immune checkpoint blockade (ICB) antibodies. We also observed that high MRTF signaling in human melanoma is associated with ICB efficacy in patients. Using biophysical and functional assays, we showed that MRTF overexpression rigidified the filamentous actin cytoskeleton and that this mechanical change rendered mouse and human cancer cells more vulnerable to cytotoxic T lymphocytes and natural killer cells. Collectively, these results suggest that immunosurveillance has a mechanical dimension, which we call mechanosurveillance, that is particularly relevant for the targeting of metastatic disease. •Metastatic cells with high MRTF activity are vulnerable to cytotoxic lymphocytes in vivo•Strong MRTF signaling is associated with responsiveness to immune checkpoint blockade•Cancer cells overexpressing MRTF induce stronger lymphocyte activation and cytotoxicity•MRTF makes cancer cells more stimulatory to lymphocytes by increasing their rigidity [Display omitted] Myocardin-related transcription factors promote metastatic colonization by inducing cell spreading and migration. Tello-Lafoz et al. show that the cellular stiffening that accompanies this morphologic change triggers a mechanical form of immunosurveillance in which cytotoxic lymphocytes destroy the metastatic cells.