ADAM proteases in cytokine biology: Modulators of immune signaling, inflammation and cancer

Ectodomain shedding, a post-translational process mediated primarily by A Disintegrin and Metalloprotease (ADAM) family members, represents a fundamental mechanism regulating intercellular communications. By cleaving the extracellular domains of membrane-anchored cytokines, receptors, growth factors, and adhesion molecules, ADAM proteases dynamically shape cytokine signaling networks that underpin immune regulation, inflammation, and tissue homeostasis. Among these enzymes, ADAM10 and ADAM17 are key effectors whose tightly controlled activity ensures the fine-tuning of pro- and anti-inflammatory pathways. Dysregulated ADAM function perturbs cytokine gradients and receptor availability, contributing to the pathogenesis of cancer, autoimmune disorders, and chronic inflammatory diseases. In this review, we provide updated perspectives on the mechanisms governing ADAM activation and substrate selectivity, including prodomain processing, trafficking, interaction with protein partners, and modulation by inflammatory stimuli. We further highlight species-specific differences and genetic polymorphisms that influence ADAM expression and catalytic efficiency, emphasizing their translational relevance in precision medicine. Collectively, delineating the ADAM/cytokine signaling axis offers crucial insights into immune homeostasis and unveils novel opportunities for therapeutic intervention in cancer and immune-mediated diseases. • ADAM proteases regulate immune responses and tissue homeostasis by cleaving membrane-bound cytokines, growth factors, receptors and adhesion molecules. • ADAMs are tightly regulated through multi-level mechanisms including prodomain processing, cofactor-dependent trafficking, phosphorylation cascades, and miRNA post-transcriptional control. • Species-specific differences in ADAM substrate selectivity, expression patterns, and compensatory mechanisms highlight the importance of cross-species validation. • Dysregulated ADAM expression and activity drive disease pathophysiology including inflammatory diseases, cancer and neurodegenerative disorders. • Future therapeutic development requires structure-based rational design to achieve ADAM family selectivity.