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.