Summary Chronic GVHD (cGVHD) is the major cause of late morbidity, mortality and compromised organ function after allogeneic hematopoietic stem cell transplant (HCT). It can affect essentially all organs and tissues, including the lungs, where the disease is termed Bronchiolitis Obliterans Syndrome (BOS). BOS is a progressive, irreversible, and often fatal lung disease that occurs following HCT. BOS occurs in approximately 5-10% of HCT survivors and is considered the pulmonary manifestation of cGVHD. Approximately 10-15% of cGVHD patients will develop BOS, and less than 15% of BOS patients survive 5 years. The primary site of inflammation in BOS is the small airway, eventually leading to fibrosis. cGVHD results from a failure to achieve immune tolerance after transplant. The mechanisms responsible for the failure of tolerance are complex and involve multiple cell types, but T cells are central to this process. Resting T cells preferentially use mitochondrial oxidative phosphorylation as basal energy. In acute GVHD, donor T cells exposed to host alloantigen in an inflammatory environment rapidly differentiate and proliferate, with bioenergetic and biosynthetic needs fulfilled by reprogramming metabolism and using multiple energy sources. In cGVHD, metabolism demands are less well understood, but with the high energy demands of proliferating immune cells in cGVHD, strategies to specifically block critical metabolic pathways may prove to be a novel treatment strategy. In this Program, we focus on the critical questions that plague the field of cGVHD. We address shortcomings in our understanding of the pathogenesis of human cGVHD and our ability to prioritize the next generation of therapeutic strategies by defining the immune networks that characterize patients who develop cGVHD and interrogate the mechanisms of both success and failure of cGVHD treatment regimens. We explore the unique metabolic demands in cGVHD pathogenesis and lung injury repair and focus therapeutics on the most severe manifestation of cGVHD, BOS. We employ novel organoid cultures and immunogenomics to pinpoint the cellular and antigenic targets of BOS. We have assembled a collaborative, multidisciplinary team, uniquely poised to make significant impact in the field.