H₂S‐Mediated Gas Therapy and HSP90 Downregulation Synergically Enhance Tumor Microwave Thermal Therapy

Abstract Microwave thermal therapy (MWTT) is a novel clinical treatment of tumors via inducing thermal effect and anti‐tumor immune response, exhibiting advantages of deep penetration, minimal invasion, and high heat conversion efficiency. However, effective ablation is difficult to cover the entire tumor area, and heat‐shock protein 90 (HSP90) is often upregulated after ablation to generate heat tolerance of sublethal tumors and weaken the induced antitumor immune effect, resulting in a high rate of tumor recurrence and metastasis. Herein, a multifunctional nanoregulator of metal phenolic network‐coated ZnS (ZnS@Ga‐tannic acid, ZGT) is proposed to release H₂S for synergically enhancing MWTT. Under the costimulation of MW radiation and acidic tumor microenvironment, ZGT can improve the MW thermal effects of tumors to promote thermal damage and release H₂S to induce tumor apoptosis. The released H₂S can also inhibit the production of ATP and then downregulate the expression of HSP90, strengthening the activated systemic antitumor immune response after ablation. This nanoregulator provides a new way for achieving compensation effect for MWTT. The strategy of H₂S gas to downregulate HSP90 and positively regulate antitumor immune response introduces a novel direction for reducing the risk of tumor recurrence and metastasis after thermal therapy.