Cell-mediated immunity was first demonstrated more than a century ago by the Nobel Prize Laureate Ilya Metchnikoff. By sticking a rose thorn into starfish lar- vae, he discovered the process of phagocytosis of foreign material and described a principle mechanism of innate immunity. Although this observation was interpreted for many years as a response to a foreign body, from the current perspective it may also be considered as a host response to injury. In 1994 Polly Matzinger proposed the ‘danger theory’, which states that the immune system can distinguish between dangerous and innocuous endo- genous signals 1 . It became evident that dying, stressed or injured cells release or expose molecules on their surface that can function as either adjuvant or danger signals for the innate immune system 1–3 . These signals were later called damage-associated molecular patterns (DAMPs) 3,4 . Some DAMPs are secreted or released (such as ATP and high mobility group protein B1 (HMGB1; also known as amphoterin)) and others are exposed de novo or become enriched on the outer leaflet of the plasma membrane (such as calreticulin (CRT) and heat shock protein 90 (HSP90)). Other DAMPs are produced as end-stage degradation products (such as uric acid) during the course of cell death (TABLE 1). Most of these molecules have predominantly non-immunological functions inside the cell before their exposure on the cell surface or their secretion 1,3 . DAMPs that are released as a result of cellular stress do not always trigger an immune response: some DAMPs, such as HGMB1, can be inacti- vated by oxidation 5 , or by caspase-dependent proteolysis, as occurs with interleukin-33 (IL-33) 6 . The emission of DAMPs was initially connected with necrosis that occurred as a result of physico- chemical injury to tissues and cells 4 . However, DAMPs have recently been reported to be actively emitted from dying apoptotic cells and to have a beneficial role in anticancer therapy owing to their interaction with the immune system 7,8 . Chemotherapy and radio- therapy function, at least in part, by inducing apopto- sis. As this cell death modality was widely considered immunologically silent or even tolerogenic 9–14 , and because the US National Cancer Institute guidelines for drug screening for anticancer therapy require testing with human tumours xenotransplanted into immunocompromised mice 15 , the role of the immune system in anticancer therapy has been systematically neglected 16 . However, in the past few years, the con- cept of immunogenic cell death (ICD) has emerged, which in our opinion underlines the important role of the immune system in the efficacy of cancer therapy not only in mice but also in humans 17–19 . Cancer cell lines treated ex vivo with anthracyclines, oxaliplatin, photodynamic therapy (PDT) or γ-irradiation and then implanted subcutaneously into syngeneic immuno- competent mice, function as a cancer vaccine in the absence of any adjuvants or immunostimulatory sub- stances 4,7,8,20 . Moreover, a substantial proportion of these mice is protected against subsequent rechallenges with live cancer cell lines. Further research has shown that DAMPs, such as surface exposed CRT, secreted ATP and passively released HMGB1, and their interac- tions with phagocytosis receptors, purinergic receptors 1 Molecular Signalling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, VIB-Ghent University Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium. 2 Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium. 3 Cell Death Research & Therapy Unit, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Leuven B-3000, Belgium. 4 The Upper Airway Research Laboratory, Department of Oto-Rhino-Laryngology, Ghent University Hospital, UZ Gent, MRB, Ghent B-9000, Belgium. *These authors contributed equally to this work. Correspondence to D.V.K. and P.V.  e-mails: Dmitri.Krysko@dmbr. ugent.be; Peter.Vandenabeele@ dmbr.vib-ugent.be doi:10.1038/nrc3380 Published online 15 November 2012 Immunogenic cell death and DAMPs in cancer therapy Dmitri V. Krysko 1,2 *, Abhishek D. Garg 3 *, Agnieszka Kaczmarek 1,2 , Olga Krysko 4 , Patrizia Agostinis 3 *and Peter Vandenabeele 1,2 * Abstract | Although it was thought that apoptotic cells, when rapidly phagocytosed, underwent a silent death that did not trigger an immune response, in recent years a new concept of immunogenic cell death (ICD) has emerged. The immunogenic characteristics of ICD are mainly mediated by damage-associated molecular patterns (DAMPs), which include surface-exposed calreticulin (CRT), secreted ATP and released high mobility group protein B1 (HMGB1). Most DAMPs can be recognized by pattern recognition receptors (PRRs). In this Review, we discuss the role of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in regulating the immunogenicity of dying cancer cells and the effect of therapy-resistant cancer microevolution on ICD. REVIEWS 860 | DECEMBER 2012 | VOLUME 12 www.nature.com/reviews/cancer © 2012 Macmillan Publishers Limited. All rights reserved