Targeting immunogenic cell stress and death for cancer therapy

Immunogenic cell death (ICD), which results from insufficient cellular adaptation to specific stressors, occupies a central position in the development of novel anticancer treatments. Several therapeutic strategies to elicit ICD - either as standalone approaches or as means to convert immunologically cold tumours that are insensitive to immunotherapy into hot and immunotherapy-sensitive lesions - are being actively pursued. However, the development of ICD-inducing treatments is hindered by various obstacles. Some of these relate to the intrinsic complexity of cancer cell biology, whereas others arise from the use of conventional therapeutic strategies that were developed according to immune-agnostic principles. Moreover, current discovery platforms for the development of novel ICD inducers suffer from limitations that must be addressed to improve bench-to-bedside translational efforts. An improved appreciation of the conceptual difference between key factors that discriminate distinct forms of cell death will assist the design of clinically viable ICD inducers. Immunogenic cell death (ICD) is crucial for the elicitation of anticancer immune responses by therapy, but the successful development of ICD-inducing treatments is hindered by various obstacles. This Review provides an overview of the core mechanisms of ICD, discusses obstacles to the development of novel ICD modulators and assesses established and innovative therapeutic approaches for ICD induction.