MacIver, N. J. | bioRxiv Science

bioRxiv2026

Obesity and Tumor Development Reprogram the Proteome and Metabolic Effects of Adipose- and Tumor-Derived Extracellular Vesicles

Obesity alters systemic metabolism and immune function, yet how obesity and tumor progression regulate extracellular vesicle (EV) composition and function within the tumor microenvironment remains unclear. Using a preclinical model of diet-induced obesity (DIO) and triple-negative breast cancer (TNBC), we investigated how obesity and tumor stage shape the proteomic composition of EVs from visceral adipose tissue (VAT-EVs) and mammary tumors (tumor-EVs), and how these EVs regulate immune and tumor cell metabolism. Orthotopically transplanted metM-Wntlung tumors were classified as early ([~]0.5 cm3) or late ([~]1.0 cm3), and EV proteomes were analyzed by mass spectrometry. At early stages, tumor-EVs from DIO mice, compared with control lean mice, were depleted in immune-related proteins, whereas VAT-EVs were enriched in mitochondrial and fatty acid oxidation proteins. In contrast, at later stages, tumor-EVs from DIO mice were enriched in lipid metabolism and oxidative stress-associated proteins, while VAT-EVs exhibited loss of mitochondrial proteins consistent with metabolic dysfunction. Functionally, tumor-EVs and VAT-EVs differentially regulated CD8 T cell mitochondrial activity and cytokine production and induced distinct, stage-dependent metabolic reprogramming in non-aggressive epithelial-like (E-Wnt) versus mesenchymal-like (M-Wnt) tumor cells. These findings suggest that obesity and tumor progression dynamically reshapes EV cargo, enabling EV-mediated metabolic reprogramming that may contribute to immune suppression and TNBC progression.

cancer biology↗

bioRxiv2020

Metabolic and functional impairment of CD8+ T cells from the lungs of influenza-infected obese mice

BackgroundObesity increases influenza disease risk in millions of adults worldwide. In this study, we investigated the effect of diet-induced obesity on pulmonary CD8+ T cell metabolism and function as a mechanism of impairment. MethodsMale C57BL/6J mice were fed either control (10% kcal/g) or high-fat (60% kcal/g) diet. Sub-lethal A/PR/8/34 influenza virus infection generated a robust pulmonary immune response. T cell metabolism and function were assessed at day 10 and day 24 post infection. ResultsAt day 10 post infection, CD8+ T cells from obese mice had impaired oxidative and glycolytic metabolism, greater fatty acid uptake, and decreased effector populations and cytokine production. At infection resolution, obese mice had lower numbers of naive and central memory CD8+ T cell populations in the lungs. ConclusionDiet-induced obesity increases influenza virus pathogenesis through CD8+ T cell mediated metabolic reprogramming resulting in suppressed effector CD8+ T cell function. SummaryDiet-induced obesity impairs the metabolism of pulmonary CD8+ T cells resulting in reduced effector CD8+ T cells and cytokine production following primary influenza infection.

immunology↗