Magnetic hyperthermia therapy (MHT) has emerged as a promising anti-cancer strategy due to its precise spatial controllability and immune-activating effects. However, tumor cells can rapidly develop thermotolerance through the upregulation of heat shock proteins (HSPs), activation of the NF-κB signaling pathway, and recruitment of immunosuppressive cells, etc. Herein, we design a tumor cell membrane coated H₂S-releasing magnetic nanoplatform (CmMN@ADT) to overcome this resistance. This nanoplatform was synthesized by coordinating Fe₃O₄ nanoparticles with 1,3,5-benzenetricarboxylic acid (BTC) to form a magnetic metal organic framework (Fe₃O₄@MIL-100, MN), which was subsequently loaded with the H₂S donor ADT-OH and coated with tumor cell membranes for homotypic targeting. Upon exposure to an alternating magnetic field (AMF), the Fe₃O₄@MIL-100 core enables localized hyperthermia, while acidic tumor microenvironment triggers ADT-OH release for sustained H₂S generation. The released H₂S enhances tumor cell sensitivity to hyperthermia by inhibiting NF-κB activation and downregulating HSP expression. Suprisingly, H₂S can also augment the MN induced ferroptosis. In vitro and in vivo studies have demonstrated that CmMN@ADT effectively induces tumor ablation and elicits potent anti-tumor immune responses, ultimately achieving the inhibition of the growth of both primary and metastatic tumors. Collectively, this study presents a novel H₂S driven magnetic MOF nanoplatform that achieves dual mode synergy between H₂S Augmented MHT and ferroptosis, providing a mechanistically guided strategy to overcome tumor thermotolerance and achieve durable tumor suppression.

Photothermal therapy (PTT) provides precise and minimally invasive tumor ablation, but its clinical utility is limited by suboptimal photothermal efficiency and inadequate tumor targeting. Single-atom nanozymes (SAzymes) offer high catalytic activity and tunability, yet require further engineering to achieve effective low-dose photothermal-catalytic therapy. We developed an iron single-atom nanozyme modified with arginine-glycine-aspartic acid peptides (Fe-SA@RGD). Structural and chemical features were characterized by advanced microscopy and spectroscopy. Photothermal heating and peroxidase (POD)-like activity were quantified. Cellular uptake, intracellular ROS generation, cytotoxicity, and immunogenic cell death (ICD) biomarkers were evaluated in 4T1 cells. In vivo antitumor efficacy and biosafety were examined in tumor-bearing mice. Fe-SA@RGD showed markedly enhanced photothermal performance, reaching 51.1 °C at 15 μg mL−1 under 808 nm NIR irradiation, which is approximately 10 °C higher than unmodified Fe-SA, while preserving robust POD-like activity. At this low dose, Fe-SA@RGD induced significant ROS generation, reduced 4T1 cell viability by 75.0%, and triggered hallmark ICD features. In vivo, Fe-SA@RGD combined with NIR achieved 94.6% tumor growth inhibition with negligible systemic toxicity. Fe-SA@RGD integrates enhanced photothermal conversion and intrinsic catalytic activity to achieve low-dose, synergistic photothermal-catalytic tumor ablation and ICD induction. This multifunctional nanoplatform demonstrates potent efficacy, favorable biosafety, and strong potential for precise and immune-active cancer therapy.