Abstract
Abstract In regulatory T cells, NAC1 enhances the acetylation of FoxP3 and protect from proteasomal degradation. Elevated levels of FoxP3+ Tregs within the tumor microenvironment (TME) showed a positive correlation with poor prognosis in various cancer patients. To address this dichotomy, we studied the role of NAC1 deletion on tumor growth. Here we report that NAC1 deficiency support tumor growth by enhanced infiltration of NAC1 deficient Tregs cells. This study confirmed that NAC1 deficient intra-tumoral Tregs are metabolically more able to adapt to acidic and nutrient deficient tumor microenvironment through enhanced FoxP3 expression mediated increased lipid metabolism and mitochondrial biogenesis. These results revealed that the NAC1-FoxP3-CD36–PGC1a signal sustains survival and functional fitness in intratumoral Treg cells by modulating mitochondrial fitness, lipid metabolism and oxidative phosphorylation driven protection from lipotoxicity and metabolizing lactate in the TME. These results highlight the unexplored NAC1-FoxP3-CD36–PGC1a modulated metabolic adaptation, which allows intratumoral Treg cells to utilize lactate and fatty acid in tumors. In adoptive Tregs transfer experiment we confirmed that Treg specific NAC1 deficiency is sufficient and a key factor to support tumor initiation and growth. This study that targeting metabolic adaptation in intratumoral Treg cells would be a hopeful strategy for reprogramming the TME.
Published Version
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