Abstract
TNF is a central regulator of immune responses, inflammation and programmed cell death, and has an essential role in maintaining tissue and immune homeostasis. Abnormal TNF signalling is implicated in a broad spectrum of physiological and pathological processes, as exemplified by monogenic disorders arising from dysregulation of core components of the TNF pathway. These rare conditions encompass various autoinflammatory syndromes, immunodeficiencies, autoimmune diseases and neurodegenerative conditions, and offer unique insights into the molecular mechanisms driving pathology via TNF-mediated inflammation and cell death. Collectively, these diseases underscore the importance of tightly regulated TNF signalling for immune balance and illustrate how distinct molecular defects can produce overlapping clinical phenotypes. Variability in pathway integration and tissue-specific gene expression further shapes disease presentation, whereas disruption of post-translational modifications and cell-death regulators have emerged as central pathogenic mechanisms. Together, these insights highlight the need for precise genetic and mechanistic understanding to inform diagnosis and therapeutic strategies.
Key points
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Gain-in-function and loss-of-function mutations in key components of the TNF pathway disrupt inflammatory and cell-death signalling, causing autoinflammatory, immunodeficiency, autoimmune and neurodegenerative disorders.
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Anti-TNF therapies are widely used in chronic inflammatory diseases but do not address all aspects of TNF-related monogenic diseases.
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The role of TNFR2 in TNF-mediated pathology is frequently underappreciated and warrants more attention.
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Murine models have provided valuable insights into disease mechanisms; however, the influence of genetic background and environmental context — often absent in controlled settings — must not be overlooked.
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TNF signalling interconnects apoptosis, necroptosis and pyroptosis and dysregulation of this network can exacerbate inflammatory responses.
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RIPK1 is an important regulatory node linking cell death and inflammation, representing a promising target for therapeutic intervention.
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Acknowledgements
N.L. was supported by the NHMRC (GNT2017929) and by the Peter MacCallum Cancer Foundation. S.L.M. was supported by the NHMRC (GNT2008699 and GNT2035298). We apologize to those whose work was not included owing to space constraint.
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Lalaoui, N., Masters, S.L. Monogenic disorders of the TNF signalling pathway. Nat Rev Rheumatol 22, 8–25 (2026). https://doi.org/10.1038/s41584-025-01327-5
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DOI: https://doi.org/10.1038/s41584-025-01327-5
