Unleashing the Potent Antitumor Force: A Reactive Oxygen Species (ROS) Storm Formation by Ultrasound-Activatable
Qi Xiang1, Yan Zhang1, Yuhong Ren1
1Chongqing Key Laboratory of Ultrasound Molecular Imaging and Therapy, Ultrasound Department of the Second Affiliated Hospital, Institute of Ultrasound Imaging, Chongqing Medical University, Chongqing, China.
Abstract:
Reactive oxygen species (ROS)-mediated tumor therapy, which induces oxidative stress damage for precise oncolysis, represents a novel antitumor strategy. However, the overexpression of glutathione (GSH) in the tumor microenvironment (TME) forms a strong antioxidant barrier, rapidly scavenging ROS and repairing oxidative damage, thus limiting the efficacy of conventional ROS-based therapies. Metal nanosonosensitizers, activated by ultrasound and penetrating deeply into the TME, offer a promising solution when combined with glutaminase1 (GLS1) inhibitors to overcome GSH-mediated defenses. This study innovatively constructs a biomimetic metal nanosonosensitizer, CRIM, with a copper sulfide as core, encapsulating IR780 and IPN60090, coated with tumor cell membranes. CRIM specifically accumulates in tumor cell mitochondria, where ultrasound activation triggers efficient ROS generation while depleting GSH levels by direct consumption and indirect synthesis. This synergistic GSH depletion disrupts the tumor antioxidant system, sustaining ROS accumulation and triggering a ROS storm. The "ROS generation-GSH depletion-exacerbated oxidative stress" feedback loop induces immunogenic cell death (ICD). Additionally, copper ion released from CRIM induces cuproptosis, synergizing with ROS-mediated cytotoxicity to enhance therapeutic efficacy. This approach triggers a ROS storm via multi-pathway synergy, induces comprehensive tumor destruction, and activates systemic immunity, thereby unleashing a potent antitumor force and offering a new direction for cancer treatment.
Insights
This study introduces CRIM, a novel biomimetic nanosonosensitizer that overcomes tumor antioxidant defenses. CRIM triggers a ROS storm and cuproptosis for enhanced cancer therapy and systemic immunity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Reactive oxygen species (ROS)-mediated therapy is limited by glutathione (GSH) in the tumor microenvironment (TME).
- Overexpressed GSH scavenges ROS and repairs oxidative damage, hindering conventional ROS-based cancer treatments.
- Metal nanosonosensitizers combined with glutaminase1 (GLS1) inhibitors offer a strategy to overcome GSH-mediated defenses.
Purpose of the Study:
- To develop a biomimetic metal nanosonosensitizer (CRIM) for enhanced ROS-mediated tumor therapy.
- To investigate CRIM's ability to deplete GSH and induce a ROS storm within tumor cells.
- To evaluate CRIM's synergistic therapeutic effects, including ROS-mediated cytotoxicity, cuproptosis, and immunogenic cell death (ICD).
Main Methods:
- Construction of a biomimetic nanosonosensitizer (CRIM) using a copper sulfide core, IR780 and IPN60090, coated with tumor cell membranes.
- Ultrasound activation of CRIM to induce ROS generation and GSH depletion in tumor cell mitochondria.
- Assessment of CRIM's efficacy in triggering a ROS storm, inducing ICD, cuproptosis, and systemic immunity.
Main Results:
- CRIM specifically accumulates in tumor cell mitochondria, generating ROS upon ultrasound activation.
- CRIM effectively depletes GSH levels, disrupting the tumor antioxidant system and sustaining ROS accumulation.
- The synergistic action of ROS generation and GSH depletion leads to a ROS storm, inducing ICD and cuproptosis, enhancing antitumor efficacy.
Conclusions:
- CRIM represents an innovative approach to overcome GSH-mediated resistance in cancer therapy.
- The developed nanosonosensitizer triggers a multi-pathway synergistic ROS storm, leading to comprehensive tumor destruction.
- This strategy holds promise for activating systemic immunity and offers a new direction for potent cancer treatment.
