Targeting Ion Homeostasis for Cancer Therapy: Mechanisms and Immunomodulatory Effects

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Background

Inorganic ions are vital for cellular activities and the body's health. These ions include metals (such as Ca2+, Zn2+, Mn2+, Fe2+/Fe3+, K+, Na+, and Mg2+) and non-metals (such as Cl-, CO32-, PO43-, and NO3-) ions, which not only contribute to the osmotic pressure of body fluids but also control significant functions in organism development or disease occurrence. Thus, the regulation of ion homeostasis is a powerful approach to disease treatment, especially for tumor therapy. For instance, calcium, zinc, and sodium ions can lead to cellular apoptosis. Many kinds of ions with variable values can induce cell death by generating reactive oxygen species through Fenton or Fenton-like reactions. Iron-mediated ferroptosis has been verified as a promising method for tumor treatment, which can be triggered by an overdose of zinc, manganese, and copper, besides the iron ion. It has recently been reported that excess copper can induce cellular cuproptosis, a type of newly defined regular cell death.

Likewise, the deprivation of ions can also perturb ion homeostasis and lead to cell death. For example, copper depletion inhibits neoangiogenesis and tumor metastasis. In addition, zinc depletion can lead to autophagic cell death and ferroptosis. Thus, both ion depletion and overload can be used for tumor treatment by interfering with ion homeostasis. Furthermore, ion-mediated cell killing often triggers immunogenic cell death (ICD), which stimulates the antitumor immune response. Specifically, many ions exhibit intrinsic abilities for regulating immune responses. For instance, zinc and manganese ions can boost antitumor immune responses by activating the cCAS-STING signaling pathway, while calcium ion can stimulate inflammasomes and T cells.

All considered, the disturbance of ion homeostasis (overload or depletion) may be a powerful strategy for tumor treatment and immunotherapy. However, research in ion homeostasis remains in its infancy, and there is still an urgent need to identify the mechanisms of ion homeostasis in tumor development, metastasis, treatment, and prognosis. Additionally, the potential system toxicity is another concern during ion homeostasis regulation. Furthermore, designing ionophores or biomaterials to regulate ion homeostasis with high specificity and efficacy and devising techniques for ion imaging and detection are vital to the clinical translation of ion homeostasis regulation in tumor treatments.

Potential topics include, but are not limited to, the following:

• The relationship between ion homeostasis and cancer or other diseases
• Strategies for modulating ion homeostasis for cancer treatment or other disease control
• Ion homeostasis and immune responses
• Ion-based strategies for tumor therapy and immunotherapy
• Ion/material-based catalytic tumor therapy
• Bioinformatics analysis of markers/pathways that relate to ion-mediated cell death

Keywords: Ion homeostasis, ferroptosis, cuproptosis, immunotherapy, STING

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