Lithium Enhances Ferroptosis sensitivity in melanoma cells and promotes CD8⁺ T Cell infiltration and differentiation

Lithium exposure reduces melanoma incidence and mortality, yet its therapeutic mechanisms are unclear. This study explores the effects of lithium on ferroptosis sensitivity and anti-tumor T cell response in melanoma. We found that lithium significantly enhanced RSL3-induced ferroptosis in vitro, evidenced by increased mitochondrial peroxide, lipid peroxidation, and mitochondrial abnormalities. Lithium also inhibited B16-F10 melanoma cell proliferation and migration in a dose-dependent manner. Cell cycle analysis showed lithium and RSL3 induced distinct perturbations, including G2/M and G0/G1 phase arrests. Mechanistically, lithium influenced intracellular ferrous ion levels by downregulating ferritin heavy chain (Fth1), crucial for iron homeostasis. The combination of lithium and RSL3 significantly suppressed tumor growth in mice, correlating with reduced Fth1 expression and increased iron deposition in the spleen and liver, highlighting a novel interaction between lithium and iron metabolism. Additionally, this combination enhanced CD8⁺ T cell infiltration and IFN-γ expression in the tumor microenvironment, especially among cytotoxic effector CD8⁺ T cells. These findings reveal the pro-ferroptotic and immune regulation roles of lithium, broaden our understanding of its biological roles, and propose new strategies for ferroptosis-targeted therapies in melanoma.