Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment.

Abstract

Epithelial ovarian cancer (EOC) incidence and mortality increase with age, driven in part by chronic inflammation, diminished T cell output, and heightened regulatory T cell (Treg) mediated immunosuppression. In aged EOC-bearing mice, we observed reduced survival, accompanied by impaired CD4⁺ and CD8⁺ T cell responses and a marked expansion of FOXP3⁺ Tregs exhibiting elevated IL-10 and TGFβ expression. Metabolic profiling revealed enhanced oxidative phosphorylation in Tregs from aged mice, along with a fivefold increase in intracellular succinate levels. This accumulation of succinate within the aged tumor microenvironment was found to potentiate Treg suppressive function. Notably, pharmacologic inhibition of α-ketoglutarate dehydrogenase reversed this effect, restoring effector T cell activity. These findings highlight succinate-driven metabolic reprogramming as a central mechanism of age-related Treg dysfunction in EOC and suggest that targeting succinate metabolism may offer a promising strategy to rejuvenate antitumor immunity in elderly patients.