CD8⁺ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4

Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)γ in combination with arachidonic acid (AA) induces immunogenic tumor ferroptosis, serving as a mode of action for CD8⁺ T cell (CTL)-mediated tumor killing. Mechanistically, IFNγ stimulates ACSL4 and alters tumor cell lipid pattern, thereby increasing incorporations of AA into C16 and C18 acyl chain-containing phospholipids. Palmitoleic acid and oleic acid, two common C16 and C18 fatty acids in blood, promote ACSL4-dependent tumor ferroptosis induced by IFNγ plus AA. Moreover, tumor ACSL4 deficiency accelerates tumor progression. Low-dose AA enhances tumor ferroptosis and elevates spontaneous and immune checkpoint blockade (ICB)-induced anti-tumor immunity. Clinically, tumor ACSL4 correlates with T cell signatures and improved survival in ICB-treated cancer patients. Thus, IFNγ signaling paired with selective fatty acids is a natural tumor ferroptosis-promoting mechanism and a mode of action of CTLs. Targeting the ACSL4 pathway is a potential anti-cancer approach.