Mefloquine enhances the efficacy of anti-PD-1 immunotherapy by inducing ferroptosis in melanoma and lung cancer cells through the IFN-γ-STAT1-IRF1-LPCAT3 pathway. The study shows that Mefloquine (Mef) promotes lipid peroxidation and ferroptosis by upregulating the expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key gene involved in lipid metabolism. This process is mediated by the activation of IFN-γ-induced STAT1-IRF1 signaling. When combined with IFN-γ, Mef significantly enhances tumor ferroptosis and sensitizes melanoma and lung cancer cells to anti-PD-1 immunotherapy. Mechanistically, Mef increases LPCAT3 expression, which is essential for lipid peroxidation and ferroptosis. Clinical data and single-cell RNA sequencing analysis indicate that lower LPCAT3 expression is associated with reduced response to anti-PD-1 immunotherapy in melanoma patients. The study also demonstrates that Mef enhances the immune microenvironment and T-cell function, leading to improved immunotherapy outcomes. These findings suggest that Mef is a promising new agent for enhancing the efficacy of anti-PD-1 immunotherapy by promoting ferroptosis through the IFN-γ-STAT1-IRF1-LPCAT3 pathway.Mefloquine enhances the efficacy of anti-PD-1 immunotherapy by inducing ferroptosis in melanoma and lung cancer cells through the IFN-γ-STAT1-IRF1-LPCAT3 pathway. The study shows that Mefloquine (Mef) promotes lipid peroxidation and ferroptosis by upregulating the expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key gene involved in lipid metabolism. This process is mediated by the activation of IFN-γ-induced STAT1-IRF1 signaling. When combined with IFN-γ, Mef significantly enhances tumor ferroptosis and sensitizes melanoma and lung cancer cells to anti-PD-1 immunotherapy. Mechanistically, Mef increases LPCAT3 expression, which is essential for lipid peroxidation and ferroptosis. Clinical data and single-cell RNA sequencing analysis indicate that lower LPCAT3 expression is associated with reduced response to anti-PD-1 immunotherapy in melanoma patients. The study also demonstrates that Mef enhances the immune microenvironment and T-cell function, leading to improved immunotherapy outcomes. These findings suggest that Mef is a promising new agent for enhancing the efficacy of anti-PD-1 immunotherapy by promoting ferroptosis through the IFN-γ-STAT1-IRF1-LPCAT3 pathway.