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Introduction and objectives Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare lung disorder with limited treatment options. Abnormal proliferation of pulmonary neuroendocrine cells (PNEC) results in the formation of tumourlets and lymphocytic infiltrates. The pathogenesis and role of immune cells in DIPNECH remains poorly understood. We hypothesise that immune cells with dysregulated metabolism are recruited to the DIPNECH lung where they drive PNEC dysfunction.Methods Peripheral blood was collected from 11 DIPNECH and 7 control patients (sex/age matched). Circulatng granulocytes, lymphocytes and myeloid cells were identified using flow cytometry. Single Cell ENergetIc metabolism by profiling Translation inHibition (SCENITH) was used to investigate metabolic in T cell subsets. To explore the lung/tumour microenvironment immunohistochemistry and histological analysis was performed using 12 DIPNECH and 13 control biopsy samples.Results In the peripheral blood, while populations of granulocytes and myeloid cells remained unchanged, reduced frequencies of T/B lymphocytes were detected in DIPNECH samples compared to controls. Interestingly, CD71 surface expression was significantly elevated on CD4+ T lymphocytes from DIPNECH patients. CD71 is a key mediator of cellular iron uptake, suggesting that iron transport in the periphery may be dysregulated in DIPNECH. The amount of CD69, a marker of early T cell activation, was higher on CD8+ T cells from DIPNECH patients compared to controls. Mitochondrial dependence, glycolytic capacity and fatty acid/amino acid oxidation were measured in both control and DIPNECH patient T cells. We detected tumourlets (Chromogranin A+) near small bronchioles and lymphocytic recruitment in DIPNECH patient lung biopsies. This was accompanied by alterations in proteins that regulate cell size, proliferation, metabolism and mTOR signalling (RPS6 and 4EBP1). Altered metabolism in recruited immune cells may promote lung PNEC cell survival/proliferation via immune-epithelial crosstalk. Taken together, our data suggest both systemic and tissue-specific immune alterations in DIPNECH accompanied by alteration in cellular metabolism.Conclusions Altered metabolism and metabolic plasticity in immune cells may promote adjacent lung PNEC proliferation and dysfunction. Disrupting this interaction may be a novel treatment for DIPNECH.