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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. [ABSTRACT FROM AUTHOR]

Microwave (MW) thermal therapy has been developed as an effective clinical strategy that can achieve pronounced antitumor activity and also has the potential to trigger antitumor immunity. However, patients generally face high rates of tumor recurrence following MW treatment, limiting the long-term benefits of such treatment. The combination of MW treatment and immunomodulatory strategies may represent a promising means of reprogramming the immunosuppressive tumor microenvironment (TME) in a manner conducive to lower recurrence rates. In this study, a Lenvatinib-loaded Gd/Fe metal-organic framework (Gd/FeMOF) was designed as a promising approach to enhancing such antitumor immunity. MW-enhanced dynamic Gd/FeMOF sensitization can facilitate high levels of reactive oxygen species production under MW irradiation, resulting in stronger immunogenic tumor cell death. In parallel, the Lenvatinib released from Gd/FeMOF preparations can serve as an immune adjuvant that suppresses programmed death ligand 1 (PD-L1) expression and drives the reprogramming of the immunosuppressive TME. The Gd and Fe present within this MOF preparation also imbue it with magnetic resonance imaging capabilities. Importantly, in vivo animal model experiments confirmed the ability of GdFeMOF treatment to significantly enhance antitumor immunity while protecting against recurrence. Accordingly, this study offers a foundation for promising strategies aimed at the integrated diagnosis and durable treatment of cancer. High rates of tumor recurrence following MW thermal therapy limit the long-term benefits of such treatment. We found that the administration of Lenvatinib-loaded Gd/FeMOF nanoparticles significantly reduced tumor recurrence after MW thermal therapy. Under MW irradiation, the Gd/FeMOF nanoparticles were found to augment the immune response due to facilitation of the process of immunogenic cell death. In addition, the released Lenvatinib could act as an immune adjuvant to downregulate the expression of PD-L1 and reprogram the immunosuppressive state of the tumor microenvironment, thus further enhancing the immune response. This is significant because MW-induced immune responses are relatively weak and usually fail to effectively prevent tumor recurrence. The combination of MW treatment with an immunomodulatory strategy may solve this problem. [Display omitted] [ABSTRACT FROM AUTHOR]