FIGURE 3.

The interaction cycle of ICI therapy and ferroptosis. Activated CD8 T cells with anti-PD-L1 therapy release IFN-γ, which downregulates the expression of SLC3A2 and SLC7A11 via the IFN-γ-JAK1-STAT1 pathway and promotes cancer cell ferroptosis. Meanwhile, activated CD8 T cell mediates apoptosis of target cancer cell via Fas-FasL pathway or granzyme B-perforin pathway. The apoptotic cell expresses receptor tyrosine kinase TYRO3 on its membrane. Once TYRO3 binds to Pros1 or Gas6 expressed on apoptotic blebs, TYRO3-PI3K-AKT pathway is activated, which leads to upregulation of pro-ferroptosis genes such as SLC3A2 and GPX4, inhibition of cancer cell ferroptosis, and cancer cells resistance to anti-PD-1 therapy. Ferroptotic cancer cells are with immunogenicity, and they release DAMPs such ATP, DNA, HMGB and so on, which promote DC maturation, a critical link of cancer-immunity cycle, and finally explaining that ferroptosis helps ICI therapy. IFN-γ, interferon-γ; JAK1, Janus-activated kinase 1; STAT1, signal transducer and activator of transcription 1; Pros1, Protein S1; Gas6, growth-arrest-specific 6; PI3K, phosphatidylinositol-4,5-bisphosphate3-kinase; AKT, protein kinase B; HMGB, high mobility group protein B; DC, dendritic cell; PD-L1, programmed cell death 1; PD-L1, programmed cell death ligand 1.