Perturbing Organelle-Level K⁺/Ca²⁺ Homeostasis by Nanotherapeutics for Enhancing Ion-Mediated Cancer Immunotherapy

Intracellular ions are involved in numerous pivotal immune processes, but the precise regulation of these signaling ions to achieve innovative immune therapeutic strategies is still a huge challenge. Here, an ion-mediated immunotherapy agent (IMIA) is engineered to achieve precise spatiotemporal control of perturbing K⁺/Ca²⁺ homeostasis at the organelle-level, thereby amplifying antitumor immune responses to achieve high-performance cancer therapy. By taking in intracellular K⁺ and supplying exogenous Ca²⁺ within tumor cells, K⁺/Ca²⁺ homeostasis is perturbed by IMIA. In parallel, perturbing K⁺ homeostasis induced endoplasmic reticulum (ER) stress triggers the release of Ca²⁺ from ER and causes a decreased concentration of Ca²⁺ in ER, which further accelerates ER-mitochondria Ca²⁺ flux and the influx of extracellular Ca²⁺ (store-operated Ca²⁺ entry (SOCE)) via opening Ca²⁺ release-activated Ca²⁺ (CRAC) channels, thus creating a self-amplifying ion interference loop to perturb K⁺/Ca²⁺ homeostasis. In this process, the elevated immunogenicity of tumor cells would evoke robust antitumor immune responses by driving the excretion of damage-associated molecular patterns (DAMPs). Importantly, this ion-immunotherapy strategy reshapes the immunosuppressive tumor microenvironment (TME), and awakens the systemic immune response and long-term immune memory effect, thus effectively inhibiting the growth of primary/distant tumors, orthotopic tumors as well as metastatic tumors in different mice models.