This study investigates the mechanism by which mefloquine (Mef) enhances the efficacy of anti-PD-1 immunotherapy in melanoma and lung cancer. Mef is found to induce ferroptosis, a form of programmed cell death characterized by lipid peroxidation and reactive oxygen species (ROS) accumulation. The study demonstrates that Mef upregulates the expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key enzyme involved in lipid peroxidation, through the activation of interferon (IFN)-γ-induced STAT1-IRF1 signaling. This upregulation of LPCAT3 sensitizes tumor cells to ferroptosis and enhances their susceptibility to T-cell-mediated killing. In combination with IFN-γ, Mef significantly inhibits tumor growth and improves the efficacy of anti-PD-1 immunotherapy. Clinically, LPCAT3 expression is positively correlated with the efficacy of anti-PD-1 immunotherapy in melanoma patients. The study concludes that Mef is a promising new target for enhancing the efficacy of anti-PD-1 immunotherapy by promoting ferroptosis.This study investigates the mechanism by which mefloquine (Mef) enhances the efficacy of anti-PD-1 immunotherapy in melanoma and lung cancer. Mef is found to induce ferroptosis, a form of programmed cell death characterized by lipid peroxidation and reactive oxygen species (ROS) accumulation. The study demonstrates that Mef upregulates the expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key enzyme involved in lipid peroxidation, through the activation of interferon (IFN)-γ-induced STAT1-IRF1 signaling. This upregulation of LPCAT3 sensitizes tumor cells to ferroptosis and enhances their susceptibility to T-cell-mediated killing. In combination with IFN-γ, Mef significantly inhibits tumor growth and improves the efficacy of anti-PD-1 immunotherapy. Clinically, LPCAT3 expression is positively correlated with the efficacy of anti-PD-1 immunotherapy in melanoma patients. The study concludes that Mef is a promising new target for enhancing the efficacy of anti-PD-1 immunotherapy by promoting ferroptosis.