(784) Succinate Fuels CCR4⁺ Treg Expansion and Immune Escape in Aging Ovarian Tumors

Introduction/Rationale: Ovarian cancer (OvCa) remains the most lethal gynecologic malignancy, with older women experiencing the poorest outcomes. Aging profoundly remodels the ovarian tumor immune microenvironment (TME), promoting regulatory T cell (Treg) mediated immune evasion; however, the underlying metabolic mechanisms remain unclear.

Methods: Using young (3-month) and aged (22-month) female mice injected intraperitoneally with ID8p53⁻/⁻ OvCa cells, we investigated how age associated metabolic reprogramming influences tumor immunity

Results: Aged OvCa bearing mice exhibited accelerated tumor progression, reduced survival (median 54 vs. 72 days), decreased CD4⁺ and CD8⁺ T cells, and an expanded Treg population. Metabolomic profiling revealed increased succinate accumulation in ascites, tumor tissue, and serum of aged mice and elderly OvCa patients. Exogenous succinate enhanced CCR4⁺FOXP3⁺ Treg frequency and upregulated IL-10 and TGF-β secretion. Elevated levels of CCL22, a CCR4 ligand, were also detected in ascites from aged mice and patients, suggesting a chemokine-driven reinforcement of Treg recruitment. PBMCs from aged patients displayed an OXPHOS-reprogrammed CCR4⁺FOXP3⁺ Treg subset with heightened suppressive capacity, markedly inhibiting CD4⁺ and CD8⁺ effector cytotoxicity. Treatment with AA6, an α-ketoglutarate dehydrogenase inhibitor that blocks succinate synthesis, reduced CCR4⁺FOXP3⁺ Treg accumulation, restored effector T-cell function, and significantly prolonged survival in aged OvCa-bearing mice.

Conclusion: Together, these findings reveal a novel succinate–CCR4 metabolic–chemokine axis that drives Treg mediated immunosuppression in aged OvCa. Targeting this pathway offers a promising strategy to restore anti-tumor immunity and overcome age-related immunotherapy resistance in ovarian cancer.