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

ABSTRACT 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.