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Trained immunity in chronic inflammatory diseases and cancer

Nature Reviews Immunology volume 25, pages 497–514 (2025)Cite this article

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Abstract

A decade after the term ‘trained immunity’ (TRIM) was coined to reflect the long-lasting hyper-responsiveness of innate immune cells with an epigenetically imprinted ‘memory’ of earlier stimuli, our understanding has broadened to include the potential implications of TRIM in health and disease. Here, after summarizing the well-documented beneficial effects of TRIM against infections, we discuss emerging evidence that TRIM is also a major underlying mechanism in chronic inflammation-related disorders such as periodontitis, rheumatoid arthritis and cardiovascular disease. Furthermore, mounting evidence indicates that the induction of TRIM by certain agonists confers protective antitumour responses. Although the mechanisms underlying TRIM require further study, the current knowledge enables the experimental development of innovative therapeutic approaches to stimulate or inhibit TRIM in a context-appropriate manner, such as the stimulation of TRIM in cancer or its inhibition in inflammatory disorders.

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Fig. 1: Central and peripheral trained immunity.
Fig. 2: Induction and recall of inflammatory memory in the bone marrow: the inflammatory bone loss paradigm.
Fig. 3: Mechanisms for the exacerbation of disease by maladaptive trained myelopoiesis.
Fig. 4: Induction of central trained immunity by IL-1.
Fig. 5: Maladaptive versus beneficial trained immunity in the context of cancer.
Fig. 6: The antitumour actions of β-glucan-induced trained immunity.

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Acknowledgements

The authors’ research is supported by grants from the NIH (DE031206 and DE033643 to G.H.), the Deutsche Forschungsgemeinschaft (SFB-TRR 332, project B4 and SFB-TRR369, project C3 to T.C.), the ‘Exzellenzförderprogramm für etablierte Wissenschaftlerinnen und Wissenschaftler’ of the ‘Deutsche Krebshilfe’ (to T.C.), the Saxon State Ministry of Science, Culture, and Tourism-SMWK (Sonderzuweisung zur Unterstützung profilbestimmender Struktureinheiten der TUD to T.C.) and Spinoza grant of the Netherlands Organization for Scientific Research (to M.G.N.). The figures in the submitted version of the manuscript were created using BioRender.com.

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Authors and Affiliations

  1. Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA

    George Hajishengallis

  2. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands

    Mihai G. Netea

  3. Department of Immunology and Metabolism, LIMES, University of Bonn, Bonn, Germany

    Mihai G. Netea

  4. Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

    Triantafyllos Chavakis

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  1. George Hajishengallis
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The authors contributed equally to all aspects of the article.

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Correspondence to George Hajishengallis, Mihai G. Netea or Triantafyllos Chavakis.

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M.G.N. is scientific founder of Lemba, TTxD and Biotrip. G.H. and T.C. declare no competing interests.

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Hajishengallis, G., Netea, M.G. & Chavakis, T. Trained immunity in chronic inflammatory diseases and cancer. Nat Rev Immunol 25, 497–514 (2025). https://doi.org/10.1038/s41577-025-01132-x

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