The emerging role of iRhom pseudoproteases in cytokine biology, inflammation and cancer

The family of inactive rhomboid-like proteins (iRhoms) have emerged as essential non-catalytic modulators of membrane protein trafficking and signaling, particularly in inflammation, and cancer, through their selective regulation of the protease A Disintegrin And Metalloproteinase 17 (ADAM17). Serving as obligate cofactors, iRhoms regulate maturation, stability and substrate selectivity of ADAM17, thereby controlling the release of cytokines, growth factors and immunomodulatory receptors. Recent studies have expanded the functional landscape of iRhoms beyond ADAM17 regulation, implicating them in endoplasmic reticulum (ER) stress adaptation, innate immune activation, and the shaping of the tumour microenvironment. Dysregulated iRhom/ADAM17 signaling contributes to chronic inflammatory pathologies, resistance to immunotherapies, and tumour progression across diverse cancer types. Here, we provide insights into the molecular function, trafficking dynamics and regulatory mechanisms of iRhoms. Further, we evaluate their impact on cytokine-dependent signaling networks in inflammation and tumourigenesis. This review positions iRhoms as central coordinators of membrane-proximal signaling events and underscores their emerging relevance as disease modifiers and potential therapeutic targets in inflammatory and malignant disorders.