Table 1 The important roles of metal ions in antitumor immunology
From: Metal ions and nanometallic materials in antitumor immunity: Function, application, and perspective
Metal ion | Location | ↑↓ | Functions | Mechanisms | Applications | Refs. |
|---|---|---|---|---|---|---|
K+ | TME | ↑ | T-cell effector dysfunction; CD8+ T-cell stemness preservation | Functional caloric restriction; autophagyautophage↑; effector programs↓ | Adoptive cell transfer therapy | [68] |
Mn2+ | TME | ↑ | NK cell activation; DC function↑; CD8+ T proliferation↑ differentiation↑; M1 polarization | Sensitizes cGAS and its adaptor STING; STING-cGAMP binding affinity; type-I IFN ↑ | Innate immunity activator | |
Mg2+ | TME | ↑ | T-cell activation; T-cell effector function↑; T-cell cytotoxicity↑; Mg2 + influx acts as second messenger in TCR signaling | Increases LFA-1 outside-in signaling; directly interacts with IL-2-inducible T-cell kinase (ITK) promoting its activation | Combined with PD-1 blockade; Target Mg2+ transporters | |
Fe2+/3+ | Cancer cells | ↑ | Immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in cancer cells | CD8+ T cells secrete IFNγ; downregulates the expression of SLC3A2 and SLC7A11 | T-cell-promoted tumor ferroptosis + checkpoint blockade | [97] |
Ca2+ | CD8+ T cells | ↓ | Activation of CD8+ T cells and NLR3 inflammasomes; NK cells function↑ | CD3 phosphorylation↑; TCR signal transduction; T-cell sensitivity↑ | Store-operated Ca2+ entry (SOCE) block | |
Zn2+ | T lymphocytes | ↑ | Boosts immune functions; targets T-cell metabolism; immune surveillance | Increases in T -cell receptor-derived excision circles (TRECs) and CD4+ naïve lymphocytes | Zinc supplementation | [100] |
Cu2+ | Cancer cells | ↓ | Modulates PD-L1 expression; cancer immune evasion; CD8+ T, NK cells↑ | Inhibits phosphorylation of STAT3 and epidermal growth factor receptor (EGFR); promotes ubiquitin-mediated degradation of PD-L1 | Copper chelators | [101] |
Pt2+ | TME | ↑ | Induces increases in antigen processing machinery (APM) component expression; upregulation of immune checkpoints or impairment of T-cell function | Enhances antigen presentation and T-cell killing; increases tumor cell expression of PD-L1; impair T-cell function | Cisplatin; combination with immune checkpoint antibody | |
Au+/3+ | Immune cells | ↑↓ | Stimulates the activation and proliferation of T as well as B cells; promotes the T-cell-based anticancer immunity cycle via DC | Activates TLR3 signaling; stimulates immune cells to secrete key inflammatory cytokines; inhibits the DNA binding activity of NF-κB | Aurothioglucose; Auranofin; sodium aurothiomalate; HAuCl4 [Au(III)]; gold sodium thiomalate | [94] |