Biomimetic MOF‐Based Nano‐Immunoactivator via Disruption of Ion Homeostasis for Strengthened Tumor Microwave‐Immunotherapy

Abstract Immunogenic cell death (ICD) is a promising strategy for anticancer immunity by inducing antigen‐presenting cell maturation. However, the traditional ICD inducers, such as chemotherapeutic agents, have largely hampered their application by severe side effects and low tumor selectivity. The changes intra/extracellular ion concentrations affect the growth and metastasis of tumor cells. Interference with ion homeostasis can induce tumor cell death and elicit immune responses. Here, a biomimetic Ga‐based metal–organic framework (MOF) coated with red blood cell–platelet fusion membrane (RPM), that is, 5‐fluorouracil@GaMOF@RPM (5‐FUGR) nano‐immunoactivator, is reported as a highly efficient ICD inducer for enhanced microwave (MW)‐immunotherapy. Following intravenous administration, 5‐FUGR accumulates to tumor site via RPM biomimetic modification‐mediated long circulation and active targeting. The structure of 5‐FUGR undergoes degradation and releases Ga³⁺. MW combined with high concentrations of Ga³⁺ disrupts intracellular ion homeostasis, which leads to severe oxidative stress and intracellular Ca²⁺ retention to promote apoptosis of tumor cells. More importantly, 5‐FUGR combined with MW not only completely eradicates 4T1 primary tumors, but also induces efficient ICD, immune initiation, and memory effects to inhibit metastatic and recurrence of the tumor. Thus, 5‐FUGR, as a strong ICD inducer, provides new insights into achieving tumor immunity in combination with other therapies.