CD19-directed chimeric antigen receptor (CAR) T cells are now used to treat B-cell malignancies. Extending their use to solid tumors requires optimizing the interactions between CAR-T cells and specific cancer cell types. A recent study by Grunewald et al. examined the role of DNA methyltransferases inhibitors (DNMTi) and histone deacetylases inhibitors (HDACi) to optimize improving CAR-T cell-mediated tumor-specific cytotoxicity against bladder cancer cells.