Table 3 Potential clinical implications of ferroptosis mediating immune tolerance.
From: Ferroptosis: a double-edged sword mediating immune tolerance of cancer
Pathway | Target | Significance | Relationship between ferroptosis and immune tolerance | Mechanism | Potential therapies | Target of agent | References |
|---|---|---|---|---|---|---|---|
Co-stimulatory recepto | CD28 | GPX4 deficient Tregs contribute to ferroptosis upon T cell receptor/CD28 co-stimulation. | Ferroptosis may obstruct immune tolerance. | Induce the death of GPX4 deficient Tregs through the CD28 costimulation pathway. | Take the cancer cells with imbalanced ferroptosis defense system, GPX4 low, as target. | FSP1 inhibitors, DHODH inhibitors, GCH1 inhibitors, BH4 depletion. | |
CTLA-4 | The expression of CTLA-4 is higher in high ferroptosis scores group, but its meaning varies. | The effect of immune tolerance mediated by upregulation of CTLA-4 via ferroptosis varies in diverse tumors, which still needs to be specifically analyzed in extensive investigations | The blockade of CTLA-4 | Combined induction of ferroptosis and immune checkpoint inhibitors. | - | ||
CD40 | CD40- CD154 is the core of humoral immune response | Ferroptosis could inhibit immune tolerance | CD40-ATP-PX27 pathway | Inducing ferroptosis | FINs | ||
CD86 | The mobilization of ATP-P2X7-CD86 axis ultimately intensified T cell activation. | Ferroptosis could inhibit immune tolerance | ATP-P2X7-CD86 pathway | Inducing ferroptosis | FINs | ||
Immune checkpoint | PD-1, PD-L1 | The expression of PD-L1 has different meanings. Poor prognosis in multiple cancers including RCC and ovarian canecer. Optimistic prognosis in breast cancer and Merkel cell carcinoma.Dual value in CRC and melanoma | Ferroptosis could either inhibit or promote immune tolerance | Prostate cancer. PD-L1 is related to HnPNPL. HnRNPL knockdown could inhibit the expression of PD-L1, thus producing increased IFN-γ, which triggers ferroptosis of CRPC cells by the STAT1/SLC7A11/GPX4 signaling axis | Overcoming resistance to conventional cancer therapies | TYRO3 inhibitors+ anti- PD1 | [155,156,157, 159,160,161,162,163, 165,166,167,168, 176, 178, 181,182,183,184, 188,189,190] |
Fe3O4-siPD-L1@M-BV2 | |||||||
GW4869-meditated PD-L1-based exosomes | |||||||
zero-valent-iron nanoparticles (ZVI-NP) | |||||||
Specialized cell population | TGF-β-producing Th3 cells | TGF-β 1 could enhance ultrastructural variation in mitochondria with increased ROS and MDA | Ferroptosis may obstruct immune tolerance | GSH level and the lipid peroxidation | Prohibiting TGF-β induced ferroptosis | Low GSH level and enhanced lipid peroxidaton | |
TGF-β 2 could affect the expression of GPX4 and ACSL4 |
