CLAD: translating basic science to clinical practice.

Chronic lung allograft dysfunction (CLAD), a fibrotic manifestation of chronic rejection, remains the major barrier to long-term survival after lung transplantation. CLAD is increasingly recognised as the final common pathway of diverse alloimmune injuries, augmented by non-alloimmune insults, that culminate in irreversible airway and parenchymal remodelling. Recent advances in molecular profiling, single-cell technologies, and biomarker discovery, with corroboration by novel animal and in vitro models, are redefining CLAD pathogenesis. Emerging data implicate distinct pathways involving cytotoxic and senescent T cells, humoral alloimmunity, innate immune activation, epithelial dysfunction, aspiration, and microbial dysbiosis. These observations support a shift from clinical phenotypes such as bronchiolitis obliterans and restrictive allograft syndromes toward biologically defined endotypes that may better predict disease progression and therapeutic responsiveness. Furthermore, the recent recognition of acute lung allograft dysfunction (ALAD) as a heterogeneous syndrome highlights an opportunity to identify and characterise graft injury before irreversible fibrosis develops. Biomarkers such as donor-derived cell-free DNA, airway transcriptomic signatures, autoantibodies, epithelial injury markers and microbiome-derived signals may facilitate risk stratification, patient enrichment and endotype-guided clinical trials. This review highlights recent mechanistic and translational advances in CLAD and discusses how molecular endotyping may enable earlier diagnosis, targeted intervention and more efficient therapeutic development. We hope that these highlights will generate enthusiasm for even greater collaboration between basic and translational researchers, and optimism regarding strategies for earlier detection and treatment of CLAD.