Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for cancer treatment. Although several LSD1 inhibitors have entered clinical trials, the discovery of novel potent LSD1 inhibitors remains a challenge. In this study, the antipsychotic drug chlorpromazine was characterized as an LSD1 inhibitor (IC<sub>50</sub> = 5.135 μM), and a series of chlorpromazine derivatives were synthesized. Among them, compound <b>3s</b> (IC<sub>50</sub> = 0.247 μM) was the most potent one. More importantly, compound <b>3s</b> inhibited LSD1 in the cellular level and downregulated the expression of programmed cell death-ligand 1 (PD-L1) in BGC-823 and MFC cells to enhance T-cell killing response. An <i>in vivo</i> study confirmed that compound <b>3s</b> can inhibit MFC cell proliferation without significant toxicity in immunocompetent mice. Taken together, our findings indicated that the novel LSD1 inhibitor <b>3s</b> tethering a phenothiazine scaffold may serve as a lead compound for further development to activate T-cell immunity in gastric cancer.