NaCl‐Based In Situ Tumor Vaccine via Amplification of Ablation‐Induced Adaptive Immunity for Enhanced Microwave‐Metalloimmunotherapy

ABSTRACT Microwave (MW) ablation is a minimally invasive and efficient therapy for patients with breast cancer who are refractory to conventional treatments. However, incomplete ablation and the immunosuppressive tumor microenvironment (TME) often lead to tumor recurrence and metastasis. Herein, we report a sodium chloride‐based in situ tumor vaccine (NaCl@Fe/Al‐LDH@L‐Menthol, NLLM ISTVs) designed to enhance MW‐metalloimmunotherapy by amplifying ablation‐induced adaptive immunity. Upon intravenous administration, MW irradiation turns on the thermal response switch of L‐Menthol, which facilitates on‐demand in situ release of NaCl from NLLM ISTVs. Subsequently, the high concentrations of Na + /Cl − induce severe oxidative stress and Ca 2+ retention in tumor cells. Importantly, NLLM ISTVs combined with MW not only eradicates cancer cells but also induces potent apoptotic cell death, thereby generating robust immunogenic cell death (ICD) signals for boosting adaptive immunity. In vivo studies using primary, distant, and lung‐metastatic tumor models demonstrate potent suppression of tumor growth and metastasis with minimal systemic toxicity. These results highlight the dual action of NLLM ISTVs in direct tumor ablation and systemic immune activation, offering a promising strategy for clinical translation. This work provides a proof‐of‐concept for combining ion‐mediated metalloimmunotherapy with MW ablation to achieve robust systemic antitumor immunity.