Ion channel modulation as a strategy to enhance cancer immunotherapy: From immune cell biology to therapeutic synergies

Ion channels are increasingly recognized as key regulators of antitumor immunity, extending beyond their classical role in controlling ion movement across cell membranes. They shape T-cell receptor signaling, differentiation, proliferation, migration, cytokine production, metabolic fitness, cytotoxicity, and exhaustion. In T and NK cells, coordinated Ca²⁺ and K⁺ fluxes sustain signaling required for effective immune responses, while ion channels also regulate dendritic-cell maturation, antigen presentation, and macrophage activation. The hostile tumor microenvironment can disrupt ionic homeostasis, impairing immune-cell function and contributing to immune escape. Importantly, ion channels also regulate tumor-cell behavior. Cancer cells frequently alter ion-channel expression and activity, affecting proliferation, volume regulation, migration, invasion, apoptosis, and metabolism. Dysregulated ion signaling can therefore promote malignant progression and influence treatment response, positioning ion channels as important regulators at the interface between tumor biology and antitumor immunity.Proposed scope of the Research Topic:• Ion channels at the tumor–immune interface: role in tumor-cell vulnerability and immune-cell competence.• Targeting ion channels within the tumor microenvironment: strategies for selective modulation of ion channels to overcome local immunosuppression.• Ion channels and the functional state of tumor-reactive T cells: mechanisms regulating T-cell activation, differentiation, exhaustion, and cytotoxicity.• Ion channels in antitumor macrophage function: their contribution to macrophage activation, polarization, metabolic reprogramming, and tumoricidal activity.• Ion channels in tumor antigen presentation: their role in dendritic-cell function, antigen processing and presentation.• Ion-channel signatures of immune states: identification of channels selectively associated with effective antitumor immunity versus immunosuppressive/dysfunctional states.• Ion channels as mediators of tumor–immune communication: channels and ionic signals that regulate interactions between cancer cells and immune cells.• Ion-channel dysregulation in tumor cells: mechanisms by which altered ion channels contribute to immune escape and tumor progression.• Ion channels as therapeutic targets in cancer immunotherapy: pharmacological, genetic, and bioengineering approaches to exploit ion-channel vulnerabilities and enhance the efficacy of immune-checkpoint blockade, adoptive cell therapy, and other anticancer treatments.• Ion-channel modulation potentially to weaken the tumor while strengthening the immune response.This Research Topic aims to bring together the rapidly growing evidence that ion channels play a much broader and more exciting role in cancer than previously appreciated, sitting at the crossroads of tumor biology and antitumor immunity. Far beyond simply controlling ion fluxes, ion channels actively shape immune-cell activation, differentiation, metabolism, migration, cytotoxicity, and exhaustion, while also influencing tumor-cell proliferation, invasion, survival, and response to therapy. We therefore hope to explore how ion-channel activity in cancer cells, immune cells, and the tumor microenvironment is interconnected, and how alterations in ionic homeostasis can drive immune dysfunction and tumor immune escape. Importantly, the Research Topic should go beyond describing these emerging roles and focus on the underlying mechanisms and, most importantly, on the therapeutic opportunities they may offer. A key goal is to highlight innovative strategies to selectively manipulate ion channels and exploit their potential to strengthen antitumor immunity and improve the efficacy of existing cancer therapies. Topic editors: Consuelo Amantini, Florina Zakany Source: https://www.frontiersin.org/research-topics/83702/ion-channel-modulation-as-a-strategy-to-enhance-cancer-immunotherapy-from-immune-cell-biology-to-therapeutic-synergies