Abstract PS3-12-22: Tumor cell AADAT suppresses CD8+T cell function by depleting malate, driving progression in Triple-Negative Breast Cancer

Abstract Triple-negative breast cancer (TNBC) remains refractory to most targeted therapies and is characterized by a profound immunosuppressive tumor microenvironment. Leveraging integrated transcriptomic, metabolomic, immunohistochemical, and clinical datasets, we identify the mitochondrial kynurenine-pathway enzyme α-aminoadipate aminotransferase (AADAT) as a previously unrecognized metabolic immune checkpoint in TNBC. AADAT transcripts and protein were significantly up-regulated in human TNBC specimens and showed a strong inverse correlation with intratumoral CD8+ T-cell abundance and patient survival. shRNA-mediated silencing of AADAT in orthotopic murine TNBC models curtailed primary tumor growth and distant metastasis in a CD8+ T-cell-dependent fashion, augmented effector T-cell activation, and rendered tumors exquisitely sensitive to combined PD-1/CTLA-4 blockade. Mechanistically, AADAT loss decreased mitochondrial CoQ10 pools, triggering a compensatory rise in secreted malate that directly boosted CD8+ T-cell oxidative metabolism, reactive oxygen species generation, and production of TNF-α and IFN-γ via an increased NAD+/NADH ratio. Exogenous malate recapitulated the antitumor effects of AADAT knockdown and synergized with paclitaxel plus anti-PD-1 therapy to suppress tumor burden and prolong overall survival. Consistent with these preclinical findings, higher intratumoral malate levels in TNBC patient cohorts associated with enhanced functional CD8+ T-cell infiltration, reduced T-cell exhaustion signatures, and superior post-chemotherapy outcomes. Collectively, these data position AADAT as a critical metabolic orchestrator of immune escape in TNBC and nominate malate supplementation as a readily translatable adjuvant strategy to amplify the efficacy of existing chemo-immunotherapy regimens. Citation Format: M. Chatterjee, F. Gu, L. Yu, D. Varghese, J. Park, B. Piyarathna, S. Thota, W. Zhang, Y. Gao, U. Rasaily, Y. Qiu, V. Putluri, B. Karanam, N. Chandandeep, B. Simons, J. Asirvatham, A. Rao, C. Morrison, G. Das, C. Ambrosone, E. Seeley, B. Kaipparettu, I. Kurland, N. Putluri, Q. Zhu, X. Zhang, A. Sreekumar. Tumor cell AADAT suppresses CD8+T cell function by depleting malate, driving progression in Triple-Negative Breast Cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-12-22.