doi:10.1186/s12967-024-05739-xengSoler-Agesta, R.Moreno-Loshuertos, R.Yim, C. Y.Congenie, M. T.Ames, T. D.Johnson, H. L.Stossi, F.Mancini, M. G.Mancini, M. A.Ripollés-Yuba, C.Marco-Brualla, J.Junquera, C.Martínez-De-Mena, R.Enríquez, J. A.Price, M. R.Jimeno, J.Anel, A.Cancer cell-selective induction of mitochondrial stress and immunogenic cell death by PT-112 in human prostate cell linesART-2024-140296PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study.2024http://zaguan.unizar.es/record/14539110.1186/s12967-024-05739-xhttp://zaguan.unizar.es/record/145391oai:zaguan.unizar.es:145391info:eu-repo/grantAgreement/ES/MICINN/PID2019-105128RB-I00Journal of translational medicine 22, 1 (2024), 927 [17 pp.]by-nc-ndhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.esinfo:eu-repo/semantics/openAccess