Immune cell-based therapy, particularly genetically modified T cells such as CAR-engineered T cells has shown promise in treating certain blood cancers. However, clinical utility of CAR-engineered T cells in the context of solid tumors has been questionable. The therapeutic efficacy of T cell-based therapy can be compromised by tumor-associated deleterious immunosuppressive molecules such as TGFβ and/or Prostaglandin E2 (PGE2). These inhibitory signals can dampen the activity of T cells, impeding the anticancer functions of T cells. Many studies have focused on PD-1 or CTLA-4 blockade to invigorate T-cell functions through CD28/B7 signaling, however obtaining robust clinical outcomes remains challenging. To overcome inhibitory tumor-associated microenvironment, we propose downregulation of diacylglycerol kinase (DGK), as it metabolizes diacylglycerol (DAG) to phosphatidic acid (PA) to regulate T cell function. For this, we utilized CRISPR/Cas9 to knockout of two different isoforms of DGKs (DGKα and DGKζ) that are expressed in human T cells. Knockout of DGKs augmented the effector functions of CAR-T cells in vitro via increased TCR signaling. DGKs knockout from CAR-T cells rendered them resistant to soluble immunosuppressive factors such as TGFβ and PGE2 and sustained effector functions under conditions of repeated tumor stimulation. Moreover, DGK knockout caused significant regression of several solid tumor models through enhanced effector functions of either CAR-engineered or TCR-engineered T cells in a xenograft mouse model. Collectively, our study shows that knockout of DGKs effectively enhances the effector functions of CAR-T cells, suggesting that CRISPR/Cas9-mediated knockout of DGK could be applicable as part of a multifaceted clinical strategy to treat solid cancers.