PARP inhibition generates enhanced CD8⁺ central memory T cells by transcriptional and metabolic reprogramming

CD8⁺ central memory T (T_CM) cells provide stronger antitumor immunity than more-differentiated effector memory counterparts. Here we show that poly(ADP-ribose) polymerase (PARP) inhibition induces CD8⁺ T_CM cells with superior memory by activating the SIRT-1-FOXO1 pathway and inducing metabolic and transcriptional switches through inhibition of enzymatic activity and enhanced PARP trapping. Together, this results in suppression of the cell cycle and upregulation of memory and fatty acid oxidation gene expression, and reprogramming CD8⁺ T cells into T_CM cells with enhanced metabolic fitness and substantially higher recall capabilities. PARP inhibitor treatment of tumor-bearing mice resulted in an increase in the number of 'superior T_CM' cells within the tumor microenvironment and enhanced immune-mediated antitumor responses. PARP inhibitor-treated CD8⁺ T cells were more effective in adoptive cell therapy. Furthermore, the frequency of CD8⁺ memory T cells and the expression of their memory markers was increased in patients with cancer treated with PARP inhibitor. Together, these data show that PARP inhibition directly reprograms CD8⁺ T cells, enhancing metabolic fitness and generating highly effective therapeutically superior memory cells.