Mary Priyanka Udumula, Km Anjaly, Faraz Rashid, Mohammad Nematullah, Harshit Singh, Tanya Bhardwaj, Miriana Hijaz, Shailendra Giri, Eduardo N Chini E, Heather M Gibson H, Ramandeep Rattan
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.