AADAT-Driven Metabolic Control of Malate and CoQ₁₀ Shapes Immune Evasion in Triple-Negative Breast Cancer

CoQ₁₀ supplementation restored metabolic balance and reversed malate accumulation caused by AADAT knockdown, indicating that AADAT helps maintain CoQ₁₀-supported redox homeostasis, thereby preventing malate buildup and export. Notably, malate addition directly boosted CD8⁺ T-cell oxidative metabolism, increased the NAD⁺/NADH ratio and reactive oxygen species, and augmented TNF-α and IFN-γ production. In vivo, malate supplementation in drinking water phenocopied AADAT knockdown, restored the response to paclitaxel plus anti–PD-1 therapy in multiple independent syngeneic TNBC models with de novo or acquired resistance to immunotherapy, reduced tumor burden, and prolonged survival.

In patient cohorts, higher spatially clustered intra-tumoral malate is associated with co-localization of functional CD8⁺ T cells, decreased exhausted T-cell neighborhoods, and superior post-chemotherapy outcomes. These data position AADAT as a central metabolic orchestrator of immune escape in TNBC and nominate oral malate as a readily translatable adjuvant to reverse chemo-immunotherapy resistance in TNBC.