Immunogenic Cell Death: From Mechanistic Insights to Pharmacological Intervention and Drug Discovery

Immunogenic cell death (ICD) is a form of regulated cell death that not only eliminates stressed, damaged, or malignant cells but also actively alerts and engages the host immune system. Cells undergoing ICD expose or release damage-associated molecular patterns (DAMPs), including calreticulin, ATP, high-mobility group box 1 (HMGB1), and type I interferons, which recruit and activate dendritic cells and prime antigen-specific T-cell responses. Initially characterized in the context of anticancer chemotherapy, radiotherapy, and oncolytic virotherapy, ICD is now recognized as relevant to cancer, infectious, autoimmune, cardiovascular, and neurodegenerative diseases. Pharmacological modulation of ICD therefore offers a strategy to convert dying cells into endogenous vaccines and creates new opportunities for drug discovery well beyond oncology. Within the scope of Experimental Pharmacology and Drug Discovery, this Research Topic focuses specifically on how defined pharmacological agents engage specific molecular targets — receptors, enzymes, ion channels, transporters, and transcription factors — to trigger or modulate ICD, and on the mechanistic characterization of such agents.Despite substantial progress, translating ICD into clinical benefit remains challenging. Key obstacles include the context-dependent nature of DAMP signaling, the lack of standardized assays and biomarkers to quantify ICD in vitro and in vivo, an incomplete understanding of how ICD interacts with immunosuppressive microenvironments, and the scarcity of rationally designed ICD-inducing agents. Moreover, the contribution of ICD to non-malignant diseases and its crosstalk with other regulated cell death pathways, such as apoptosis, necroptosis, pyroptosis, and ferroptosis, are only beginning to be appreciated. This Research Topic aims to bridge mechanistic exploration and pharmacological application by bringing together studies that dissect the molecular machinery of ICD and those that exploit it for therapeutic intervention, from target validation and compound screening to biomarker development and combination immunotherapy.We welcome contributions covering the molecular mechanisms of ICD and DAMP release; the screening and characterization of ICD-inducing compounds, including repurposed drugs and other well-defined small molecules; the role of ICD in cancer and non-malignant diseases, where a defined pharmacological intervention and its mechanism of action are investigated; standardized in vitro and in vivo assays and biomarkers that support target validation and compound characterization; and combination strategies with immune checkpoint inhibitors or other immunotherapies.We invite Original Research, Review, Mini-Review, Perspective, and Brief Research Report articles. Specific themes of interest include, but are not limited to:• Molecular mechanisms and hallmarks of immunogenic cell death• DAMPs and their receptors: signal transduction and immune activation• Pharmacological inducers of ICD: small molecules and nanomedicines• Crosstalk between ICD and other regulated cell death pathways and its therapeutic implications• ICD in cancer immunotherapy and rational combination treatment strategies• Roles of ICD in infection, autoimmunity, and other non-malignant diseases, addressed through pharmacological intervention• Assays, biomarkers, and preclinical models supporting the development of ICD-targeting agentsIn line with the scope of the Experimental Pharmacology and Drug Discovery section, submissions must provide experimental evidence on the interaction between the agent under study and its specific biological target(s). Studies on crude extracts, multiherbal preparations, or natural products, purely in silico work without experimental validation, clinical trials, and patient prognosis studies fall outside the scope of this Research Topic. Manuscripts claiming anti-cancer effects should provide, as a minimum, in vitro evidence in two cell lines. This Research Topic supports SDG 3: Good Health and Well-being. Topic editors: Yalin Tu, Christophe Glorieux Source: https://www.frontiersin.org/research-topics/85213/immunogenic-cell-death-from-mechanistic-insights-to-pharmacological-intervention-and-drug-discovery