Danger signals in immunity: new molecules, receptors and concepts from tissue stress to cancer immunology

Since its introduction by Polly Matzinger, the Danger Theory has profoundly reshaped modern immunology. Rather than relying solely on a self/non-self framework, immune activation is now understood as a context-dependent process driven by signals of tissue stress, damage, dysregulated homeostasis, and environmental perturbation. These signals—including pathogen- and damage-associated molecular patterns (PAMPs/DAMPs), alarmins, metabolites, oxidative and mechanical cues—provide essential information that guides whether immune cells initiate attack, tolerance, or repair. In healthy tissues, controlled fluctuations in metabolism, microbiota-derived cues, and physiological cell turnover help maintain immune tolerance. In cancer, where chronic stress, immunogenic cell death, and tumor-driven remodeling coexist, danger-associated signaling becomes even more complex, influencing inflammation, immune evasion, and therapeutic response. As new molecules, receptors, and cell-type-specific circuits continue to be discovered, revisiting the Danger Theory in light of contemporary molecular and cellular immunology is both timely and necessary.This Research Topic aims to address the central question raised by the Danger Theory: how does the immune system interpret signals of tissue stress to decide what is dangerous, particularly in the context of cancer? Despite major advances, the complexity of this issue remains poorly understood. Immune cells perceive an ever-expanding repertoire of endogenous and exogenous cues, yet how these signals integrate across tissues, cell types, and temporal scales is still not well known. This collection seeks to bring together studies that identify novel danger-associated molecules and receptors, map ligand–receptor networks, and dissect downstream signaling pathways in myeloid cells, lymphocytes, tissue-resident immune cells, and non-immune stromal compartments within the tumor microenvironment. Particular emphasis is placed on understanding how danger signals regulate tumor microenvironment remodeling, immune evasion, and response or resistance to therapy. Selected contributions from infection, autoimmunity, transplantation, mucosal and metabolic immunology, and tissue repair will be considered where they provide conceptual or mechanistic insights relevant to cancer immunity. Ultimately, the goal is to refine, challenge, or extend the Danger Theory within cancer biology and cancer immunity using modern mechanistic, computational, and translational approaches. This Research Topic welcomes original research, methods, reviews, Mini Reviews, Perspectives, and Hypothesis & Theory articles. We encourage submissions addressing:• Identification and characterization of new danger-associated molecules, alarmins, and stress signals• Novel receptors, pattern-recognition pathways, and ligand–receptor interaction networks• Cell-type-specific signaling circuits in dendritic cells, macrophages, neutrophils, ILCs, tissue-resident lymphocytes, stromal or parenchymal cells• Roles of danger signaling in cancer: immunogenic cell death, TME reprogramming, immune evasion, trained immunity, and therapy response• Conceptual or computational models refining or challenging the Danger Theory, including integration with self/non-self frameworks• Cross-disciplinary studies in infection, autoimmunity, transplantation, neuro-immune and metabolic stress, and tissue repair relevant to cancer immunology. Topic editors: Francisco J Cueto, Paola Brandi Source: https://www.frontiersin.org/research-topics/77079/danger-signals-in-immunity-new-molecules-receptors-and-concepts-from-tissue-stress-to-cancer-immunology