H₂S‐Activated Ion‐Interference Therapy: A Novel Tumor Targeted Therapy Based on Copper‐Overload‐Mediated Cuproptosis and Pyroptosis

Abstract

Copper overload is a novel way to achieve copper‐ion‐interference therapy by disrupting copper homeostasis and treating diseases through multiple cell death pathways. However, it is difficult to reach copper overload since excess intracellular copper ions will be pumped out. Herein, copper overload is achieved by both raising cellular uptake and reducing the efflux of copper ions using hydrogen sulfide (H2S)‐responsive copper hydroxyphosphate nanoparticles (Cu2(PO4)(OH) NPs). After immersion in an H2S‐enriched colon cancer microenvironment, Cu2(PO4)(OH) NPs can transform into copper sulfide NPs with reduced size for higher cell entering, resulting in improved Fenton activity as well as copper ion dissociation. Reactive oxygen species generated by the Fenton reaction not only activate inflammasomes and Caspase‐1 proteins, cause the cleavage of gasdermin D to induce pyroptosis, but also affect mitochondrial function and down‐regulate copper exporter ATP7A to further reduce the copper excretion. The combination of higher endocytosis and lower exportation leads to maximized copper overload. Together with the efficient copper ions release, mitochondrial tricarboxylic acid cycle can be disrupted and iron‐sulfur cluster proteins are downregulated, ultimately triggering cuproptosis. As both pyroptosis and cuproptosis are efficient ways to induce cell death, this study provides a novel way to realize effective tumor‐targeted therapy based on H2S‐activated copper overload with simple Cu2(PO4)(OH) NPs.

Cuproptosis: Harnessing Transition Metal for Cancer Therapy

“…It is noteworthy that the targeted design of environmentally responsive nanomedicines can be tailored to the unique TME of different tumors. Zhao et al demonstrated using Cu 2 (PO 4 )­(OH) nanoparticles, capable of converting into CuS nanoparticles within the H 2 S-rich TME of colon cancer . This characteristic maximizes copper ion uptake by the tumor and reduces damage to normal tissues …”

“…151 This characteristic maximizes copper ion uptake by the tumor and reduces damage to normal tissues. 151 Nanodrugs Targeting Metabolism. As previously mentioned, the occurrence of cupropostosis is intricately linked to cellular metabolism.…”

“…Zhao et al demonstrated using Cu 2 (PO 4 )(OH) nanoparticles, capable of converting into CuS nanoparticles within the H 2 S-rich TME of colon cancer. 151 This characteristic maximizes copper ion uptake by the tumor and reduces damage to normal tissues. 151 Nanodrugs Targeting Metabolism.…”

“…160 Thus, the rational design of combination therapy strategies that trigger multiple forms of cell death associated with ROS is beneficial for cancer treatment. Based on this premise, a range of cell death modalities, including apoptosis, 150,153 pyroptosis, 151 ferroptosis, 150 and autophagy, 161 have been utilized to enhance cuproptosis.…”

Biomaterials Elicit Pyroptosis Enhancing Cancer Immunotherapy

“…[99] By coordinating natural polyphenols and chemically synthesized polyphe-nol derivatives with metal ions, Dai's group constructed a metalpolyphenol coordination nanomedicine PWE, which converted radiation therapy-mediated apoptosis into pyroptosis through epigenetic methods and then stimulated systemic antitumor immune response. [100] Yu et al [101] suggested a copper overload strategy using H 2 S to accumulate copper ions in colon cancer cells. This approach enhances cellular uptake and reduces copper ion efflux, enabling effective and selective treatment of colon cancer through cuproptosis and pyroptosis.…”