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.