DADA inhibits tumor growth by enhancing CD8+ T cell stemness

To elucidate the mechanism by which DADA enhances the CD8+ T cell anti-tumor immune responses, we performed signal-cell RNA-sequencing (scRNA-seq) on tumor-infiltrating CD45+ T cells isolated from ctrl- or DADA-treated MC38-bearing mice.In this study, we found that diisopropylamine dichloroacetate (DADA) enhances CD8⁺ T cell-mediated anti-tumor immunity and promotes the accumulation of Tpex cells in the tumor microenvironment.

Mechanistically, DADA promotes the conversion of pyruvate to acetyl-CoA by inhibiting pyruvate dehydrogenase kinase, thereby increasing oxidative phosphorylation (OXPHOS) levels and mitochondrial fitness, and ultimately enhancing the stemness of CD8⁺ T cells. In mouse models, DADA treatment significantly improves the efficacy of PD-1 blockade. Furthermore, the addition of DADA to the in vitro expansion system of chimeric antigen receptor (CAR)-T cells confers stemness characteristics to the cells, thereby enhancing their anti-tumor efficacy.