Cystic Fibrosis and Colorectal Cancer Risk: Reprogramming of the Intestinal Epithelial Niche and Cell-State...

Cystic fibrosis (CF) has shifted from a fatal paediatric lung disease to a multi-organ, lifespan-spanning disorder in which gastrointestinal (GI) complications and malignancies are increasingly prominent. With improved survival into mid- and late adulthood, aided by newborn screening, optimised nutrition and the advent of highly effective CF transmembrane conductance regulator (CFTR) modulators, implementation of colonoscopic surveillance has highlighted a several-fold increase in early-onset colorectal cancer (CRC) and a broader spectrum of intestinal pathology. In parallel, work in mouse models, human tissue and patient-derived intestinal organoids now places the CFTR at the centre of a complex epithelial compartment that integrates ion and pH homeostasis, mucus biology, microbiota, redox balance and immune/stromal function. In this review, we advance the hypothesis that CF may be conceptualised as a niche-centric hereditary CRC predisposition syndrome, in which germline CFTR dysfunction chronically destabilises epithelial identity in addition to increasing mutational burden. We synthesise evidence that CFTR loss remodels stem cell regulation, promotes hypoxia and oxidative stress, perturbs microbial ecosystems, drives chronic immune activation and stromal remodelling, and induces epithelial-mesenchymal plasticity (EMP) and DNA-damage vulnerability, collectively creating a pre-neoplastic intestinal ecosystem. We situate this model within contemporary CRC frameworks that emphasise cell-state transitions, hybrid epithelial-mesenchymal (E/M) states and specialised stromal niches, and we distinguish it from oncofoetal reprogramming, an APC-driven programme that CF does not clearly recapitulate. We propose that CF may provide a naturally occurring human context in which chronic epithelial stress sustains EMP-like pressure, a concept that requires direct validation in human CF intestinal tissue. Finally, we consider how CFTR modulators, microbiome-directed therapies and redox-targeted interventions might re-programme the CF intestinal niche and outline experimental and clinical strategies needed to determine whether early, ecosystem-level correction can prevent GI cancers in this high-risk population.