This article systematically reviews the dual roles of trained immunity in infection, chronic inflammation, and cancer, revealing its central position as a common pathological mechanism in diseases, and proposes novel therapeutic strategies targeting trained immunity.
Literature Overview
This article, 'Trained Immunity in Chronic Inflammatory Diseases and Cancer,' published in Nature Reviews. Immunology, reviews and summarizes the critical roles of trained immunity (TRIM) in infection defense, chronic inflammatory diseases, and cancer. The article systematically elaborates on the molecular mechanisms of TRIM, particularly epigenetic reprogramming in hematopoietic stem and progenitor cells (HSPCs), known as 'central trained immunity,' and highlights that this mechanism not only mediates long-term protective immunity but can also drive comorbidities across multiple chronic inflammatory diseases. Furthermore, the article discusses the potential benefits of TRIM in anti-tumor immunity as well as its paradoxical role in promoting immunosuppression within the tumor microenvironment. The study further emphasizes that targeting signaling pathways such as IL-1β may represent a strategy to modulate TRIM for treating inflammatory diseases or enhancing cancer immunotherapy. The entire section is coherent and logically structured, ending with a Chinese period.Background Knowledge
Trained immunity (TRIM) refers to the phenomenon where innate immune cells acquire a long-term enhanced responsiveness after exposure to pathogens or their components, through metabolic and epigenetic reprogramming, distinct from the memory characteristics of adaptive immunity. TRIM can be induced by agents such as β-glucan and Bacillus Calmette-Guérin (BCG), primarily through histone modifications that alter chromatin accessibility, enabling rapid transcription of inflammatory-related genes upon restimulation. Recent studies have revealed that TRIM not only occurs in mature myeloid cells (peripheral TRIM) but can also take place in hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, forming 'central TRIM,' whose effects can last for months or longer, explaining how TRIM can influence long-term immune states. In the context of infection, TRIM provides heterologous protection—for example, BCG vaccination reduces the risk of non-tuberculous infections. However, in chronic inflammatory conditions such as periodontitis, rheumatoid arthritis, and atherosclerosis, persistent systemic inflammation can induce central TRIM in HSPCs, leading to the continuous production of hyperresponsive myeloid cells that exacerbate distal tissue damage, forming an immunological basis for disease comorbidity. Additionally, TRIM exhibits duality in cancer: on one hand, it can enhance anti-tumor immunity; on the other, it may promote tumor progression by inducing immunosuppressive myeloid cells. Targeting regulatory mechanisms of TRIM, such as the NLRP3/IL-1β pathway, has become a promising direction for treating chronic inflammation and cancer. This study integrates recent breakthrough findings from animal models and clinical research, providing an important theoretical framework for understanding the mechanisms of chronic diseases and developing novel immune interventions.
Research Methods and Experiments
The study comprehensively analyzed experimental data from multiple mouse models and human clinical studies, with a focus on using bone marrow transplantation techniques to validate the causal role of central trained immunity. In a periodontitis-arthritis comorbidity model, after inducing periodontitis via ligation (LIP), researchers transplanted bone marrow from affected mice into healthy recipients and found that the recipients exhibited more severe inflammation in a subsequent arthritis model, indicating that trained immunity can propagate across tissues. Similar approaches applied to models of myocardial infarction, stroke, obesity, and diabetes consistently confirmed that trained HSPCs exacerbate pathological processes such as atherosclerosis, cardiac fibrosis, and kidney injury. Mechanistically, epigenetic analyses using ChIP-seq and ATAC-seq revealed that IL-1β and the NLRP3 inflammasome signaling pathway play a central role in inducing trained immunity. In human studies, PET/CT imaging showed a positive correlation between bone marrow hematopoietic activity and arterial inflammation in patients with periodontitis, supporting the role of central TRIM in human disease comorbidities. Additionally, analysis of cytokine secretion capacity in peripheral blood monocytes from patients with coronary artery disease and periodontitis revealed hyperresponsiveness upon in vitro restimulation, suggesting the presence of trained immune memory. In cancer models, the study compared the effects of BCG or β-glucan treatment on tumor growth and analyzed phenotypic changes in tumor-associated myeloid cells.Key Conclusions and Perspectives
Research Significance and Prospects
This study systematically reveals the central role of trained immunity in the network of chronic diseases, providing a unified mechanistic explanation for the clinical phenomenon of 'one inflammation, multiple affected sites.' Central TRIM, as an immunological memory hub for disease comorbidity, suggests that intervening in bone marrow immune reprogramming may become a novel strategy for treating multiple chronic diseases.
Drugs targeting key nodes of trained immunity, such as IL-1β (e.g., canakinumab), have already demonstrated reduced inflammatory events in cardiovascular disease; this study provides a new mechanistic explanation for their effects and supports their potential application in diseases such as periodontitis and arthritis. Moreover, the duality of trained immunity suggests the need for fine-tuned regulation in cancer immunotherapy: enhancing beneficial TRIM (e.g., vaccine adjuvants) or suppressing harmful TRIM (e.g., chronic inflammation-associated immunosuppression) may become directions for personalized therapy.
Future research should further explore the specific induction mechanisms of trained immunity, develop selective regulatory strategies, and validate trained immunity biomarkers in clinical cohorts as predictors of disease risk or treatment response. Additionally, the regulatory effects of lifestyle interventions (e.g., exercise, sleep) on trained immunity warrant deeper investigation, providing a theoretical basis for non-pharmacological interventions.
Conclusion
This article comprehensively summarizes the dual roles of trained immunity in health and disease, emphasizing that it is not only a crucial mechanism for host defense but also a key driver of comorbidity in chronic inflammatory diseases and cancer progression. By integrating animal models and human studies, the article establishes central trained immunity as the core of systemic inflammatory memory, mediated by epigenetic reprogramming of HSPCs and regulated via the IL-1β/NLRP3 signaling pathway. This mechanism explains why localized inflammation (e.g., periodontitis) can increase pathological risks in distal organs (e.g., heart, joints). In cancer, the coexistence of protective and tumor-promoting effects of trained immunity suggests that its regulation must be context-dependent. The study calls for the development of novel therapies targeting trained immunity, such as inhibiting IL-1β to alleviate chronic inflammation or using inducers like BCG to enhance anti-tumor immunity. Furthermore, the long-lasting nature of trained immunity suggests that early intervention may alter disease trajectories. This review provides an important theoretical framework for the fields of immunometabolism, chronic diseases, and cancer immunotherapy, promoting a shift from 'single-disease' to 'systemic immune state' management, with profound clinical translational potential.
