Beyond Innate: Trained Immunity and Memory-like Responses in NK Cells

The concept of trained immunity has redefined innate immune responses as adaptable, durable, and context dependent. Natural killer (NK) cells, traditionally viewed as short-lived effectors, are now recognized to acquire memory-like properties following cytokine stimulation, viral exposure, and metabolic reprogramming. These trained NK states are characterized by sustained epigenetic remodelling, altered transcriptional networks, and enhanced functional outputs, including cytokine production and cytotoxicity. Distinct forms of NK cell training—cytokine-induced memory-like responses and virus-driven adaptive NK cells—highlight the diversity and specificity of this phenomenon. Emerging evidence further implicates metabolic cues, such as shifts in α-ketoglutarate and oxidative pathways, in shaping NK cell fate and function. These insights position trained NK cells at the intersection of innate and adaptive immunity, with profound implications for cancer immunotherapy, infectious diseases, and transplantation. This special issue aims to consolidate current advances and inspire new directions in harnessing NK cell memory for therapeutic innovation.A central challenge in NK cell biology is to define the molecular and contextual determinants that distinguish beneficial aspects of trained NK cell states from dysfunctional, exhausted, or tolerized states across disease settings. Despite rapid progress in advanced technologies, the integration of epigenetic, transcriptional, and metabolic programs, the molecular basis of NK cell memory remains incomplete. Recent advances-including single-cell multi-omics, chromatin accessibility profiling, and cytokine-induced memory-like NK cell platforms-now enable high-resolution dissection of these states in both human and mice. This Research Topic seeks to consolidate these insights and promote studies that functionally validate trained NK programs, and potentially translate these principles into next-generation NK cell–based therapies for cancer, infection, and transplantation.This Research Topic will provide a comprehensive platform to define, dissect, and translate trained immunity in natural killer (NK) cells, spanning fundamental mechanisms to clinical applications. We aim to bring together studies that clarify how NK cells acquire, maintain, and functionally deploy memory-like states across physiological and pathological contexts.Key Themes of Interest• Molecular and epigenetic mechanisms of NK cell trainingChromatin remodeling, enhancer dynamics, DNA methylation, and transcriptional circuitry governing trained states. • Cytokine-induced and infection-driven NK cell memoryComparative analyses of cytokine-induced memory-like (CIML) NK cells and virus-adapted NK populations (e.g., CMV-associated). • Immunometabolism in trained NK cellsMetabolic rewiring (glycolysis, OXPHOS, TCA intermediates such as α-ketoglutarate) and its role in shaping NK cell function and fate. • Heterogeneity and state transitionsSingle-cell and multi-omics approaches to resolve NK cell subsets, developmental trajectories, and trained vs regulatory/tolerized states. • Trained NK cells in disease contextsRoles in cancer, chronic infection, autoimmunity, and transplantation (including graft-versus-host disease). • Therapeutic exploitation of trained NK cellsAdvances in adoptive NK cell therapies, cytokine priming strategies, CAR-NK platforms, and combination immunotherapies. • Integration of innate and adaptive immune featuresConceptual frameworks redefining NK cells at the interface of innate training and adaptive memory. We welcome a broad range of article types, including:• Original Research Articles (mechanistic, translational, or clinical studies) • Review Articles (comprehensive or focused thematic reviews) • Methods Articles (novel experimental or computational approaches) • Clinical Trial Reports and Translational Studies Collectively, this Research Topic aims to define the principles of NK cell training and accelerate their application in immunotherapy and disease modulation. Topic editors: Subramaniam Malarkannan, Barbara L Kee Source: https://www.frontiersin.org/research-topics/82426/beyond-innate-trained-immunity-and-memory-like-responses-in-nk-cells