Ca²⁺ is the most abundant metal ion involved in the proliferation and cycling of immune cells. Currently, Ca²⁺ is the most studied metal ion and widely recognized as a second messenger in immune responses (12). This section will discuss the transport and effect of Ca²⁺ in lymphocytes.

The concentration gradient of Ca²⁺ is involved in release and storage and dependent on Ca²⁺ release-activated Ca²⁺ (CRAC) channels, transient receptor potential (TRP) channels, P2X and Ca_v channels. After the engagement of immunoreceptors, the mitogenic signal emanating from the IS induces the breakdown of PIP2 to inositol trisphosphate (IP3) binding to the IP3 receptors resulting in the release of Ca²⁺ from the endoplasmic reticulum (ER), and activates stromal interaction molecules (STIM1/2) to bind to the N- and C-termini of ORAI1 which form the subunit of the CRAC channel (13). The CRAC channel exhibits a notable preference for Ca²⁺ and possesses remarkably low single-channel conductance (14, 15). The influx of Ca²⁺ into intracellular organelles is mediated by store-operated Ca²⁺ entry (SOCE) (16, 17) ( Figure 1 ).

T cells activated by tumor antigens in an MHC-I-restricted manner begin to proliferate and release cytokines. During this progression, signal transduction considerably relies on key receptors and signaling molecules, including evocation and termination (18). IP3 binds to the IP3 receptor, resulting in Ca²⁺ influx to activate the calcineurin-nuclear factor of activated T (NFAT) pathway, which enhances the cellular processes, for example, polarization, proliferation, and cytokines release including interleukin 2 (IL-2), interferon-γ (IFNγ), tumor necrosis factor (TNF), perforin, and granzyme (19, 20). Abolishment of humanT cell function is caused by deletion of STIM1 or ORAI1 to inhibit Ca²⁺ influx in vitro (21). Functional CRAC channels and elevated levels of cytoplasmic Ca²⁺ may activate leukocyte function-associated antigen 1 (LFA-1), contributing to the adhesion of cytotoxic lymphocytes (CTLs) to the target cells both in vitro and in vivo (22–24). Co-receptor CD5 co-cross-linking with the TCR-CD3 complex down-regulated the TCR-CD3-increased Ca²⁺ mobilization to inhibit T cell function (25). Programmed death-1 (PD1) blockade increases Ca²⁺ signaling to enhance the migratory ability of CTLs in neck cancer (26). P2X, a type of Ca²⁺ channels, enhances T cell function and T cell receptor (TCR) signaling both in human and mouse model (27, 28). TRP and Ca_v channels promote rodent and human T cells differentiation and proliferation (29–32) ( Table 1 ).

Tregs protect organisms from autoimmune reactions by maintaining T cell tolerance (60). Inhibition or depletion of Tregs enhances the efficacy of cancer immunotherapy (33). Deficiency of either STIM1 or STIM2 in T cells leads to differentiation to Treg, Th1and Th17 cells suggesting that STIM is vital for their development and function (34).

Natural killer (NK) cells originate from bone marrow stem cells, undergo two differentiation and maturation pathways in the bone marrow and thymus, and are widely distributed in the main organs. NK cells selectively kill target cells, such as viral infections or tumors, and play an important role in anti-tumor immunity (35, 36, 61, 62). The ablation of either RAI1 or STIM1 in NK cells severely impairs defective store-operated Ca²⁺ entry but not cytotoxic granule polarization (63, 64). After interaction with target cells, the release of cytokines, such as TNF-α, granulocyte-macrophage colony stimulating factor (GM-CSF), and interferons, by NK cells is increased via the calcineurin-NFAT-dependent pathway (65, 66). Increasing the intracellular Ca²⁺ concentration of dendritic cells (DCs) boosts autophagy and promotes antigen presentation (67). High intracellular Ca²⁺ levels inhibit the formation of WIP/WASP droplets, allowing PKC-θ to easily access and phosphorylate WIP, thereby increasing the actin polarization of macrophages and phagocytosis of tumor cells (68) ( Figure 2 ).

Ca²⁺ can bind directly to anionic phospholipids, acting as a regulator for membrane protein functionality. A pH-responsive calcium carbonate nanoparticle (CaCO3/CAI@Liposome, CCL) was prepared by loading calcium carbonate nanoparticles with CAIX inhibitors (CAI) and coating with liposomes, which can accurately regulate the content of Ca²⁺ and pH in and out of tumor cells to promote DCs maturation and macrophage polarization towards the anti-tumor M1 type (69). Given the positive role of Ca²⁺ in immune cells, novel methods should be explored to utilize Ca to improve its anti-tumor effects.

Zn²⁺ is a trace metal essential for several proteins and plays a vital role in cell proliferation, differentiation, oxidative stress, immune responses, and apoptosis by conjugating to zinc-binding proteins (37, 70, 71). Moreover, Zn²⁺ participates in various pathophysiological processes, including growth retardation, cognitive disorders, cardiovascular diseases, and cancer (72).

Zn²⁺ homeostasis is tightly regulated by two families of Zn²⁺ transporters: ZnTs and ZIPs (72). ZnTs contain10 members contributing to the export of Zn²⁺ from the intracellular space. ZIPs have 14 members that facilitate an increase in the cytosolic concentration of Zn²⁺ (73). Metal regulatory transcription factor 1 (MTF-1) is sensitive to Zn²⁺ and activated via cysteine2-histidine2 (Cys2-His2) Zn fingers binding to DNA to mediate the expression of ZnT1, ZnT2, and metallothioneins (MTs), which regulate the storage and release of intracellular Zn²⁺ (74, 75) ( Figure 1 ).

In the T cell response, the MAPK, PI3K/Akt, and STAT3 pathways are the main signal target transducers of Zn²⁺ which regulate the expression of genes involved in differentiation, survival, proliferation, and apoptosis. ZIP6 expression is enhanced by the activation of the STAT3 signaling pathway to mediate cell migration (38, 39, 76). In sickle cell anemia, Zn²⁺ deficiency decreases CD73, a marker of cytotoxic T cells, resulting in suppressing T cell differentiation and maturation (77, 78). In addition, interaction between the domain of CD4 or CD8α with p56^lck is also controlled by Zn²⁺ in regulating T cell activation and differentiation in vitro (79). Zap70, a TCR signaling downstream molecule, is phosphorylated through activating Zn²⁺ regulated kinase to sustain proliferation and activation in mouse spleen and thymus cells, as well as human Jurkat T cells. Moreover, Zn²⁺-dependent TCR signal amplification induces IL-2 receptor expression, leading to proliferation of activated T cells (76). In contrast, ZIP6 deletion impairs activation marker expression and cytokine production (80–82). Additionally, SLC39A6 indirectly promotes cell proliferation and cytokine production via TCR activation (83). Moreover, MTs and zinc-finger transcription factors are increased to regulate tumor infiltrating lymphocytes (TILs) in mouse model (40). TILs up-regulate GATA-3 and IKZF2 to mediate Zn²⁺ homeostasis inducing T-cell differentiation and exhaustion in the B16F10 murine melanoma model (84). The balance of T helper cell differentiation is altered by Zn²⁺ signaling. Zn²⁺ depletion decreases IFNγ and T-bet essential for Th1 differentiation in Con-A stimulated HUT-78 cells (41, 84).. TH17 and Treg cells formation is mediated by Zn²⁺ supplementation which remits the T cell-mediated allogeneic immune responses in the human mixed lymphocyte reaction (85, 86). GLI-similar 1 (GLIS1), a zinc finger protein, causes CD8⁺ T cell exhaustion via the SGK1-STAT3-PD1 pathway in hepatocellular carcinoma (HCC) (87). Zinc finger protein 64 (ZFP64) is a transcription factor for cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti- PD-1 in esophageal cancer (88, 89) ( Table 1 ).

In addition to affecting T cells, Zn²⁺ can also regulate other immune cells. In mature DCs, the importers ZIP6/10 are decreased, whereas ZnT1/4/6 and MTs are increased to reduce intracellular Zn²⁺ (90). Unlike in DCs, an increase of Zn²⁺ activates macrophages and the recruitment of neutrophils (91). In NK cells, Zn²⁺ promotes the lytic activity and differentiation (92) ( Figure 2 ).

Zn²⁺ is essential for innate and adaptive anti-tumor immunity leading to an increase of Zn²⁺-based nanometallic materials. ZnS@BSA (bovine serum albumin), a new zinc-based nanocluster, enhances the infiltration of CD8⁺ T cells and DCs via cGAS-STING signals in HCC (93). Moreover, a Zn-metal-organic skeleton vaccine (ZPM@OVA-CpG) achieved the targeted release of Zn²⁺ in DCs and the TME under acidic conditions. The vaccine actively promoted DCs maturation and antigen cross-presentation via cGAS-STING signaling, resulting in the activation of CD8⁺ T cells (94). Weichselbaum et al. investigated ZnCDA, a powerful tumor-targeting STING agonist, which enhances tumor accumulation by destroying endothelial cells in the tumor vascular system. ZnCDA preferentially targets tumor-associated macrophages to regulate antigen processing and presentation and subsequently triggers anti-tumor T cell responses. ZnCDA reinvigorates the anti-tumor activity of radiation therapy and immune checkpoint inhibitors in immunologically “cold” pancreatic and glioma tumor models (95). Based on the effects on different immune cells, Zn²⁺ is a double-edged sword. Therefore, these factors should be carefully considered before using Zn²⁺.

Mn²⁺ is regarded as a second messenger in mammalian tissues and as an essential metal for intracellular processes, such as energy production, bone growth, reactive oxygen species (ROS) generation, and immune response (42, 96). The mobilization and distribution of Mn²⁺ is precisely mediated through gamma globulin, albumin, and Mn-transferrin complex. Mn²⁺ plays a key role in the activation of various enzymes, including glutamine synthetase (GS), isomerases, pyruvate carboxylase, arginase (ARG), lyases, and hydrolases (43, 44).

Usually, intracellular Mn²⁺ is stored in resting organelles, such as the mitochondria or Golgi apparatus. However, damage to mitochondrial activity and DNA can result in the presence of a large amount of intracellular Mn²⁺ (45, 97). Unlike Ca²⁺ and Zn²⁺, intracellular Mn²⁺ is transported using various transporters, such as divalent metal transporter A (DMT1), calcium-based proteins such as TRPM3/7, and metal-dependent proteins such as ZIP8/14 and ZnT10 (42, 98–100) ( Figure 1 ).

The effect of Mn²⁺ on T cells is mainly reflected by an increase in the number, differentiation, and cytokine release of TILs by inducing type I interferon production in a murine orthotopic HCC model (101–103). Moreover, Mn²⁺ deficiency leads to a reduction of macrophage antigen presentation and DCs maturation, thereby mediating murine CD8⁺ T cell activation in vivo (104). Furthermore, Mn²⁺ treatment substantially increases the infiltration of murine NK cells and the release of cytokines to reduce tumor growth (105, 106). Mn²⁺ can change macrophage (M2) polarization to macrophage (M1) with anti-tumor effects (107). Mechanistically, the Mn²⁺-dependent cGAS-STING pathway plays a remarkable role in T and NK cell functions and DCs maturation. It was reported that NK cell activity increased by producing type I IFNs after adding MnCl₂ (103). In addition, Mn²⁺ improved the clinical efficacy of PD-1/PD-L1 therapy (101, 108). Taken together, Mn²⁺ serves a vital function in the cross-presentation of immune cells, such as DCs, TILs, and NK cells ( Figure 2 ).

Manganese oxide (MnO₂) nanomaterials are typically used as enhancers to increase the immunotherapy efficiency of photothermal agents by catalyzing the conversion of H₂O₂ into O₂ (109). Mn@CaCO3/ICG nanoparticles serve as vectors for loading small interfering RNA (siRNA) targeting PD-L1 (109). Hou et al. designed MnO nanoparticles combined with the tumor-homing peptide iRGD (CRGDKGPD) to effectively activate the cGAS-STING signaling pathway. Manganese also assisted α-PD-1 to inhibit tumor growth and metastasis (110). Therefore, Mn²⁺ is a potential therapeutic adjuvant for the treatment of tumors.

Mg²⁺ is the second-most abundant metal ion (111, 112). Mg²⁺ is normally complexed with ATP or ADP or acts as a cofactor, which is essential in the regulation of biological activities, such as the cell cycle, apoptosis, division, and differentiation (46, 113), as well as biochemical processes, including oxidative phosphorylation, glycolysis, DNA repair, metabolism, and synthesis (114–116).

Mg²⁺ distribution is different among the extracellular and intracellular spaces, which determines its various functions. Extracellular Mg²⁺ binds to plasma proteins to transmit activating or inhibitory signals, whereas intracellular Mg²⁺ interacts with nucleotides, nucleic acids, or ATP to mediate biochemical processes (117). The Mg²⁺ transport is tightly regulated by intake and excretion via Mg transporter 1 (MAGT1), TRP cation channel subfamily M member 7 (TRPM7), SLC41A1, and Na⁺ exchange; MAGT1 is a highly selective Mg²⁺ channel (47, 118, 119) ( Figure 1 ).

Mg²⁺ is regarded as a second messenger that regulates proliferation, development, and function through MAGT1, TRPM7, and SLC41A1 transporters in T cells (48, 120),. After TCR stimulation or PLCγ1 activation, Mg²⁺ and Ca²⁺ enter T cells in an MAGT1-dependent manner (121). The deletion of MAGT1 decreases the capacity response to TCR and Ca²⁺ entry into human T cells in vitro (48, 122). In contrast, reducing the concentration of Mg²⁺ causes TCR signal suppression, resulting in human T cell exhaustion, decreased Ca²⁺ influx, proliferation, CD69 and CD25 expression both in vitro and vivo (120, 123). In addition, TRPM7, a non-selective Mg²⁺ channel, modulates Mg²⁺ concentration and T cell development and maturation (124, 125) and is fundamental for anti-tumor immunity (20, 126). Mouse TRPM7 deficiency did not affect acute uptake of Mg²⁺ or the maintenance of total cellular Mg²⁺ but suppresses T cell maturation (20, 49). Mechanistically, the binding between Mg²⁺ and metal-ion-dependent adhesion sites causes TCR signal stimulation, resulting in conformational changes in LFA-1, which is essential for T cell activation by mediating proximal and distal signaling activities, such as focal adhesion kinase phosphorylation and extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation (50, 127–129). Lotscher et al. measured serum Mg²⁺ levels in 100 patients with leukemia and 67 patients with lung cancer and found that patients with low serum Mg²⁺ levels had lower survival rates to CAR-T therapy (128) ( Table 1 ). In addition, activation and cytotoxicity are increased in intratumor CD8⁺ T cells and NK cells after intraperitoneal injection of MgCl₂ (127) ( Figure 2 ).

K⁺ is an important inorganic electrolyte used to maintain normal physiological functions in the human body. K⁺ is involved in glucose, protein, and energy metabolism. K⁺ is the main cation in the cells and involved in maintaining osmotic pressure, myocardial function, and the acid-base balance of the intracellular and extracellular fluids (51, 130).

Similar to other cations, the balance of K⁺ within cells is finely controlled by several ion channels, including Kv1.3, KCa3.1, K2p3.1, K2p5.1, and K2p9.1 (131). Kv1.3 and KCa3.1 act as the main channels. The activation of Kv1.3- and KCa3.1-dependent membrane depolarization and release of Ca²⁺ and calmodulin, respectively, results in K⁺ efflux (52).

K⁺ has a crucial role in modulating T cell function and is associated with Ca²⁺ signaling (17, 132). TCR activation signals increase Ca²⁺ entry, resulting in intracellular Ca²⁺ release and membrane depolarization that causes Kv1.3 and KCa3.1 activation to increase K⁺ efflux, which in turn restores the membrane state, resulting in Ca²⁺ entry to induce NFAT expression, IL-2 release, T cell migratory capacity, and T cell subsets, including Th1, Th2, Th17, and Treg cells (133–135). In contrast, Ca²⁺ signaling is repressed if Kv1.3 and KCa3.1 are blocked upon TCR stimulation, indicating that the K⁺ gradient and Kv1.3 and KCa3.1 channels are essential for modulating T-cell activation (136). Moreover, reducing intracellular K⁺ via overexpression of KCa3.1 can increase the production of IFNγ in T cells to inhibit tumor growth and prolong survival, which is proved in patients with head and neck cancer (26, 53). In anti-tumor T-cell responses, large amounts of K⁺ produced by necrotizing tumor cells lead to a functional decline in CD8⁺ T cells owing to increased intracellular K⁺ affecting the Akt-mTOR pathway. Adenosine (Ado) and PD-1 signaling inhibit KCa3.1channel activity to limit K⁺ efflux leading to restrain the ability of CD8⁺ T cells from cancer patients (51) ( Figure 1 ).

Another effect of K⁺ on T cells is the reprogramming of T cell metabolism. Higher extracellular K⁺ levels lead to autophagy and mitochondrial-based energy metabolism, causing changes in the expression of genes associated with activation, stemness, or exhaustion in T cells (137). In TILs isolated from B16 tumors, increasing extracellular K⁺ level induces central memory T cells, whereas reducing effector memory T cells and exhaustion markers, such as PD1, 2B4, and Tim-3 to enhance cancer immunotherapy. Hexokinase II also requires K⁺ as a cofactor to mediate anti-tumor immunity (137). In contrast, CD19-CAR-T cells express higher memory and lower effector genes after culturing in a medium containing a low glucose level and K⁺ (138) ( Table 1 ). The anti-tumor effect of high K⁺ level was reported. The underlying mechanism was attributed to inhibition of tumor-associated macrophages (TAM), and the Kir2.1 channel was identified as the central regulator of TAM functional polarization in the high K⁺ TME (139) ( Figure 2 ).

Fe^2+/3+ has several biological functions in living organisms. Iron ions are important components of hemoglobin and myoglobin, which are used to maintain normal respiratory function (140). Second, iron ions participate in the catalytic reactions of various enzymes in the body, including fatty acid metabolism and oxidases. Iron ions also regulate various important metabolic processes, such as immune responses, neurotransmission, and DNA synthesis (141, 142).

Given the importance of Fe²⁺, its transport is finely regulated. Transferrin protein (Tf) is regarded as the primary transporter that forms a complex with Fe²⁺ and internalized by the transferrin receptor (CD71) (54, 143). In addition, DMT-1 and ZIP-8 are used to transport Fe²⁺ in a nonspecific manner (143).

T cell function and activation are impaired under conditions of defective Tf-receptors or decreased intracellular Fe²⁺ levels, such as reduced expression of CD25 and impaired to IL-2 receptor signaling (144). In contrast, Fe²⁺ supplementation in the culture medium can restore the biogenesis of T cell (145). Ferroptosis is an iron-dependent form of regulated cell death in both T and tumor cells. Fe³⁺ usually binds to transferrin in the form of trivalent iron, enters cells through transferrin channels, and is reduced to Fe^{2 +} by the metal reductase STEAP3, resulting in a Fenton’s reaction that releases reactive oxygen species (ROS) represented by hydroxyl radicals. Accumulated ROS-mediated peroxidation of membrane lipids leads to damage to cell function and ferroptosis. At present, ferroptosis is regarded as a method of inhibiting tumor growth, and a close correlation has been found between ferroptosis and anti-tumor immunity (55, 146). In a recent study, CD36 expression decreased cytokine release and inhibited the anti-tumor activity of B16 tumor-infiltrating CD8⁺ T cells owing to CD36-mediated lipid peroxidation and ferroptosis (147). In contrast, CD8⁺ T cells can induce tumor ferroptosis via lipid peroxide accumulation triggered by CD8⁺ T cells-secreted IFNγ to increase STAT1 and suppress cystine/glutamate antiporter system Xc in B16 beard mouse model (148). Peng Liao et al. found that arachidonic acid and IFN-γ secreted by CD8⁺ T cells in the TME can induce MC38 and B16F10 cell ferroptosis (149) ( Figure 1 ).

According to a previous report, Fe²⁺ is released by other immune cells, such as TAMs and tumor-associated neutrophils (TANs), to sustain cancer progression (150). Fe²⁺ transporters and metabolism play an essential role in macrophage polarization; for example, M1 macrophages tend to reduce the level of Fe²⁺, whereas M2 macrophages are inclined to recirculate free Fe²⁺ (151). Kim et al. reported that myeloid-derived immunosuppressive cells (PMN-MDSCs) in the TME spontaneously induce oxidized lipid release, causing repression of T cell activity. In mice with normal immune function, suppressing ferroptosis inhibits the immunosuppressive activity of PMN-MDSCs and can be combined with immune checkpoint inhibitors to inhibit tumor growth (152). In HCC, ferroptosis triggers tumor invasion of MDSCs via high mobility group protein B1 (153). In gastric cancer, NK cell levels are negatively correlated with the abundance of tumor-associated fibroblasts (CAF). CAF impair the anti-tumor ability of NK cells by inducing ferroptosis (154) ( Figure 2 ).

Magnetic hyperthermia is a tumor therapy triggered by iron oxide nanoparticles, enabling an increase in antigen presentation, maturation of DCs, T lymphocyte recruitment, and a reduction in Tregs (155). Biocompatible PEG-coated ferrihydrite nanoparticles (PEG-Fns) mediate TAM polarization from M2 to M1 (156). Zhang et al. assembled quercetin and iron ions to prepare the nano-photosensitization agent, QFN. When QFN was decomposed, the released quercetin reduced programmed death ligand 1 (PD-L1) in tumor cells by decreasing the activation of JAK2 and STAT3 and reshaping the extracellular matrix (ECM) (157). In summary, these data indicate that iron plays a dual role in regulating immune and tumor cells.

Cu^+/2+ is an important trace element and an essential component of many biochemical reactions. There are two types, Cu⁺ and Cu²⁺ in living organisms (158). Within cells, Cu²⁺ undergo redox reactions and metabolic pathways with other metabolites, such as cytochrome c redox reactions and intracellular respiration (159). In addition, Cu²⁺ is important components of many enzymatic reactions, such as intracellular oxygen site-catalyzed oxidation reactions. Finally, Cu²⁺ participates in the expression of many transcription factors that regulate various physiological reactions, such as nuclear factor-kappa B (NF-кB) and activator protein-1 (AP-1) (160–162).

Cu²⁺ deficiency or excess can lead to oxidative stress and toxicity. Intracellular Cu²⁺ is delivered to various cellular compartments to modulate intracellular processes (163). Consequently, Cu²⁺ homeostasis is closely modulated by solute carrier family 31 member 1/2 (CTR1/2) and SLC11A2/DMT1, as well as ATPase copper transporting α (ATP7A) and β (ATP7B), MT, glutathione (GSH), Cu²⁺ chaperone for superoxide dismutase (CCS), antioxidant protein 1 (Atox1), and cytochrome c oxidase copper chaperone 17 (COX17). Extracellular Cu²⁺ is reduced to Cu⁺ by binding to metal reductases of the STEAP family and is transported into cells via SLC31A1 or combined with Cu²⁺ chaperone protein antioxidant-1 (ATOX1) to the Golgi network via ATP7A/B (164, 165). Within the cytoplasm, excess Cu²⁺ is excreted via ATP7A/B and transferred from the Golgi apparatus to other organelles to mediate cellular copper homeostasis (56). CCS1 delivers Cu²⁺ to superoxide dismutase 1 (SOD1) in the cytoplasm (57, 166). Cu⁺ in the mitochondrial membrane is regulated by COX17 during transport (167). CCS and ATOX1 are important transporters of Cu⁺ into the nucleus (168, 169). Furthermore, elesclomol, ATN-224, tetrathiomolybdate, disulfiram (DSF), pyrithione, and chloroquine are considered copper ionophores (58).

Cu²⁺ potentially is involved in the activation and regulation of T cells. Cu²⁺ deficiency impairs CTL capacity to kill target cells and reduces T cell proliferation both in vitro and in vivo (170, 171). Bala et al. found that the infiltration of CD4⁺ and CD8⁺ T cells decreased in splenic monocytes from copper-deficient rats (59). Both the protein and mRNA expression of IL-2 are reversibly decreased in human T lymphocytes, as well as superoxide anion production by neutrophils after Cu²⁺ deficiency (172–174). Moreover, the effect of Cu²⁺ on helper T cells is consistent with CTLs including their proliferation and function (175, 176). Voli et al. demonstrated that intracellular Cu²⁺ regulates PD-L1 expression to inhibit the function of T lymphocytes in brain tumors. Further exploration revealed that copper chelators decrease PD-L1 expression by suppressing the epidermal growth factor receptor (EGFR) and transcriptional activator protein (STAT) signaling pathways to increase the number of T lymphocytes and NK cells (177) ( Figure 1 ).

Like other ions, Cu²⁺ also regulate other immune cells. Chatterjee et al. demonstrated that CuNG (a copper chelate) reprogrammed TAMs from M2 to M1, activating the T cell function (178, 179). Blood neutrophils are reduced in copper deficiency by decreasing the superoxide anions (180) ( Table 1 ).

Cuproptosis is a unique mode of cell death and first reported by Tsvetkov et al. in 2022 (181–184). The classical mechanism of cuproptosis involves the binding of elesclomol to extracellular Cu²⁺ and its transport to the cellular compartment. Ferredoxin 1 (FDX1) reduces Cu²⁺ to Cu⁺ and inhibits iron-sulfur protein cluster (Fe-S) synthesis. Together, these abnormal processes lead to protein toxicity, ultimately leading to cell death. Wang et al. showed that chimeric antigen receptor T (CAR T) cells were reprogrammed by exposing DSF/Cu plus ionizing irradiation (IR). This method can reverse the immunosuppressive TME and increase the anti-tumor function of CAR-T cells (185, 186).

A nanoparticle drug, NP@ESCu, was developed to induce cancer cell apoptosis and simultaneously reprogram the immunosuppressive TME. When combined with αPD-L1 blockade, the therapeutic effect on cancer was obviously increased, which contributes to a broad range of clinical applications (187). BSO-CAT@MOF-199 @DDM (BCMD) nanomediated copper proliferation can induce immunogenic cell death (ICD) and enhance DC activation and T cell infiltration (188). In summary, although copper plays a key role in the activity of various enzymes, cytotoxicity can occur at higher concentrations.