PURPOSE: Despite favorable responses of CAR-engineered T cell therapy in patients with hematologic malignancies, the outcome has been far from satisfactory in the treatment of solid tumors, partially owing to the development of an immunosuppressive tumor microenvironment. To overcome this limitation, we engineered CAR-T cells secreting checkpoint inhibitors (CPIs) targeting PD-1 (CAR.alphaPD1-T) and evaluated their efficacy in a human lung carcinoma xenograft mouse model. EXPERIMENTAL DESIGN: To evaluate the effector function and expansion capacity of CAR.alphaPD1-T cells in vitro, we measured the production of IFN-gamma and T cell proliferation following antigen-specific stimulation. Furthermore, the antitumor efficacy of CAR.alphaPD1-T cells, CAR-T cells, and CAR-T cells combined with anti-PD-1 antibody was determined using a xenograft mouse model. Finally, the underlying mechanism was investigated by analyzing the expansion and functional capacity of TILs. RESULTS: Human anti-PD-1 CPIs secreted by CAR.alphaPD1-T cells efficiently bound to PD-1 and reversed the inhibitory effect of PD-1/PD-L1 interaction on T cell function. PD-1 blockade by continuously secreted anti-PD-1 attenuated the inhibitory T cell signaling and enhanced T cell expansion and effector function both in vitro and in vivo. In the xenograft mouse model, we demonstrated that the secretion of anti-PD-1 enhanced the antitumor activity of CAR-T cells and prolonged overall survival. CONCLUSIONS: With constitutive anti-PD-1 secretion, CAR.alphaPD1-T cells are more functional and expandable, and more efficient at tumor eradication than parental CAR-T cells. Collectively, our study presents an important and novel strategy that enables CAR-T cells to achieve better antitumor immunity, especially in the treatment of solid tumors.