Fig. 3

Role of ferroptosis in tumor immunity. Immunotherapy-activated CD8⁺ T cells release IFN-γ, which transcriptionally inhibits SLC7A11 and SLC3A2 by activating JAK1-STAT1 signaling. IFN-γ also induces ACSL4 expression and promotes the generation of lipid peroxidation substrate PUFA-PLs. Immunotherapy-induced release of TGFβ1 transcriptionally represses SLC7A11 through the SMAD-involved pathway. Immunotherapy inhibits SLC7A11 synergistically with radiotherapy-activated ATM. Immunotherapy can also synergize with FINs to promote lipid peroxidation. DAMPs released by ferroptotic cells enhance antitumor immune responses by reversing the immunosuppressive microenvironment. Lipid metabolites activate macrophages immune responses and adaptive immunity-driven cytotoxic T lymphocytes. Furthermore, the release of HMGB1 during ferroptosis leads to the up-regulation of TNFα in macrophages and sustains the immune response. On the other hand, ferroptotic cells can inhibit antitumor immunity by releasing KRAS (G12D), which triggers M2 macrophage polarization. 8-OHG released by ferroptotic cells activates STING signaling in macrophages, leading to an inflammatory tumor microenvironment and causing tumorigenesis. TNFα tumor necrosis factor-alpha, DAMPs damage-associated molecular patterns, HMGB1 high mobility group protein B1, 8-OHG 8-hydroxyguanosine, IFNγ interferon-gamma, TGFβ transforming growth factor β, PD-L1 programmed cell death-ligand 1, KRAS (G12D) Kirsten rat sarcoma viral oncogene homolog-G12D mutation