Immune dyshomeostasis in lifestyle-associated diseases: a new paradigm for personalized medicine and prevention

Non-communicable diseases, including metabolic, inflammatory, and malignant disorders, now dominate global morbidity and mortality. These chronic, lifestyle-associated diseases expose the limits of strategies focused on suppressing late-stage inflammation. We argue that immune dyshomeostasis - rather than overt inflammation - represents the more actionable target in lifestyle-associated disease. Across barrier tissues, immune circuits involving innate lymphoid cells and epithelial mediators such as IL-22 preserve tissue resilience under environmental stress. Metabolic regulators, including itaconate-NRF2 signaling, further constrain inflammatory activation and reinforce immune balance. A homeostasis-first strategy emphasizes early detection of pathway drift using feasible biomarkers, assignment of corrective levers spanning lifestyle, exposure hygiene, and pharmacology, and longitudinal tracking of restoration using tissue-relevant endpoints. Proof-of-principle interventions, including immune reset in autoimmunity, demonstrate that immune set-points are druggable while underscoring the need for earlier interventions. Together, these concepts position immune homeostasis as a unifying framework for precision prevention and translational immunology.