Beyond a binary view of cystic fibrosis: systemic immunity and inflammation across the spectrum of CFTR dysfunction

ABSTRACT Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is traditionally framed within a dichotomy of health and disease, yet its systemic immune consequences across the spectrum of CFTR activity remain incompletely defined. Using multimodal immune profiling, we constructed a single-cell atlas of circulating immune cells in people with cystic fibrosis (pwCF), healthy F508del carriers and non-carriers. In pwCF, circulating immunity was markedly altered following treatment with elexacaftor-tezacaftor-ivacaftor, with broad reductions in pro-inflammatory cytokines and immune changes linked to improved clinical outcomes. Strikingly, healthy F508del carriers exhibited a CF-like immune signature characterised by low-grade systemic inflammation, including elevated IL-6, reduced mucosal-associated invariant T cells, and inflammatory monocyte features overlapping with pwCF. Together, these findings show that CFTR dysfunction spans a spectrum of systemic immune dysregulation, challenging a strict dichotomy between health and disease.