Intracellular Magnetic Nanodelivery of H 2 S and Heat Synergize to Reshape the Tumor Immune Microenvironment

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Abstract
Hydrogen sulfide (H 2 S), a recently identified gasotransmitter, has gained significant attention in cancer therapy due to its regulatory effects on cellular processes. Its clinical application, however, is limited by challenges, such as precise dosage control and eliciting effective immune responses. To overcome these hurdles, a dual‐response strategy is devised that integrates H 2 S therapy with intracellular magnetic hyperthermia (IMH) to synergistically enhance anti‐tumor immunity. This approach is centered on the development of Zn 0.4 Fe 2.6 O 4 @L‐Cys, a high‐performance nanotherm agent that responds to both the acidic lysosomal environment and an exogenous alternating magnetic field. At the tumor site, Zn 0.4 Fe 2.6 O 4 @L‐Cys nanoparticles release the H 2 S donor L‐cysteine (L‐Cys) in a controlled manner, facilitating localized H 2 S generation. This dual‐response strategy enhances anti‐tumor immunity through two key mechanisms: 1) inhibiting catalase expression and accelerating hydroxyl radical production, thereby amplifying IMH‐induced immunological effects; and 2) alleviating tumor immunosuppression by reducing myeloid‐derived suppressor cell accumulation, promoting immune cell infiltration, and selectively inducing tumor cell apoptosis. Experimental findings demonstrate that this strategy not only strengthens anti‐tumor immunity but also improves therapeutic efficacy while minimizing off‐target effects. Beyond confirming the synergy between H 2 S therapy and IMH in hepatocellular carcinoma treatment, these results provide valuable insights for developing integrated tumor treatment approaches.

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