Prepared MW-Immunosensitizers Precisely Release NO to Downregulate HIF-1 Expression and Enhance Immunogenic Cell Death

Microwave thermotherapy (MWTT) has limited its application in the clinic due to its high rate of metastasis and recurrence after treatment. Nitric oxide (NO) is a gaseous molecule that can address the high metastasis and recurrence rates after MWTT by increasing thermal sensitivity, down-regulating the expression of hypoxia-inducible factor-1 (HIF-1), and inducing the immunogenic cell death (ICD). Therefore, GaMOF-Arg is designed, a gallium-based organic skeleton material derivative loaded with L-arginine (L-Arg), and coupled the mitochondria-targeting drug of triphenylphosphine (TPP) on its surface to obtain GaMOF-Arg-TPP (GAT) MW-immunosensitizers. When GAT MW-immunosensitizers are introduced into mice through the tail vein, reactive oxygen species (ROS) are generated and L-Arg is released under MW action. Then, L-Arg reacts with ROS to generate NO, which not only downregulates HIF-1 expression to improve tumor hypoxia exacerbated by MW, but also enhances immune responses by augment calreticulin (CRT) exposure, high mobility group box 1 (HMGB1) release, and T-cell proliferation to achieve prevention of tumor metastasis and recurrence. In addition, NO can induce mitochondria damage to increase their sensitivity to MWTT. This study provides a unique insight into the use of metal-organic framework MW-immunosensitizers to enhance tumor therapy and offers a new way to treat cancer efficiently. GAT MW-immunosensitizer unifies MWTT-NO-ICD in the nanoparticle to play three birds with one stone. It precisely releases NO to downregulate HIF-1 alpha expression, which not only enhances MW thermotherapy 4T1 primary tumors, but also amplifies the ICD effect, triggering a powerful immune response and memory effect against tumor metastasis and recurrence.image