DADA Enhances CD8⁺ T Cell Stemness to Improve Anti-Tumor Immunity and Immunotherapy Efficacy.

Progenitor exhausted CD8⁺ T (Tpex) cells have recently been identified as a stem-like T cell subset that mediates durable anti-tumor immune responses and represents a pivotal population responsive to immunotherapies. Here, it is demonstrated that diisopropylamine dichloroacetate (DADA) facilitates CD8⁺ T cell-mediated anti-tumor immunity and promotes Tpex cells accumulation in the tumor microenvironment. Mechanistically, DADA promotes the conversion from pyruvate to Acetyl-CoA by inhibiting pyruvate dehydrogenase kinase. This process leads to increased oxidative phosphorylation (OXPHOS) and mitochondrial fitness, thereby enhancing CD8⁺ T cells stemness. Treatment of mice with DADA improves the efficacy of PD-1 blockade. Furthermore, the in vitro expansion of chimeric antigen receptor (CAR)-T cells supplemented with DADA confers them with stemness characteristics, contributing to improved anti-tumor efficacy. Collectively, this study illustrates how DADA-mediated metabolic reprogramming in CD8⁺ T cell enhances their stemness, underscoring its potential for anti-tumor therapy.