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ROS-Responsive Hydrogel for Localized Delivery of Nampt and Stat3 Inhibitors Exhibits Synergistic Antitumor Effects
Chenyang Ye1, Mi Mi1, Saimeng Shi1
1Department of Medical Oncology, Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, School of Medicine, Ministry of Education, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, 310009, China.
Abstract:
Targeting Nampt to modulate NAD+ metabolism and exert antitumor effects has become a research hotspot in the field of cancer metabolism. But early clinical trials have only achieved modest results, primarily due to the need for improved efficacy and the occurrence of severe systemic adverse effects. Therefore, enhancing antitumor efficacy and reducing the adverse effects of Nampt inhibitors are urgent challenges. The research reveals that the Nampt inhibitor FK866 can induce ferroptosis in colorectal cancer cells via the NAD+/Stat3/Gpx4 signaling axis. Furthermore, the combination of FK866 and the Stat3 inhibitor C188-9 demonstrates a strong synergistic antitumor effect. Importantly, a reactive oxygen species (ROS)-responsive hydrogel that encapsulates FK866 and C188-9 for in situ drug delivery, effectively reducing systemic side effects, is developed. Intriguingly, mass cytometry time-of-flight (CyTOF) analysis indicates that the combined treatment with FK866 and C188-9 exerts antitumor effects by increasing the infiltration of CD8+ T cells and neutrophils into the tumor, as well as enhancing the expression of immune-regulatory molecules, including IFN-γ, IL-10, and perforin. Thus, this localized treatment not only minimizes systemic adverse effects, but also markedly amplifies antitumor efficacy through the modulation of both tumor cells and the tumor immune microenvironment, representing a promising antitumor treatment strategy.
Insights
This study developed a novel hydrogel delivery system for Nampt inhibitors, enhancing antitumor efficacy and reducing side effects in colorectal cancer by targeting NAD+ metabolism and the immune microenvironment.
Area of Science:
- Cancer Metabolism
- Drug Delivery Systems
- Immunotherapy
Background:
- Nampt inhibitors targeting NAD+ metabolism show promise for cancer treatment but face challenges with efficacy and systemic toxicity.
- Improving antitumor effects and minimizing adverse events of Nampt inhibitors are critical for clinical application.
Purpose of the Study:
- To investigate the antitumor effects of a Nampt inhibitor (FK866) in colorectal cancer.
- To develop a localized drug delivery system to enhance efficacy and reduce side effects.
- To explore the combination therapy of FK866 with a Stat3 inhibitor (C188-9) and its impact on the tumor immune microenvironment.
Main Methods:
- Utilized FK866 to induce ferroptosis in colorectal cancer cells via the NAD+/Stat3/Gpx4 axis.
- Developed a reactive oxygen species (ROS)-responsive hydrogel for co-delivery of FK866 and C188-9.
- Employed mass cytometry time-of-flight (CyTOF) to analyze immune cell infiltration and molecular expression.
Main Results:
- FK866 induced ferroptosis in colorectal cancer cells.
- Combined FK866 and C188-9 showed synergistic antitumor effects.
- The hydrogel delivery system reduced systemic side effects and enhanced antitumor efficacy.
- Combined treatment increased CD8+ T cell and neutrophil infiltration, boosting immune-regulatory molecules like IFN-γ and perforin.
Conclusions:
- Localized delivery of combined FK866 and C188-9 via a ROS-responsive hydrogel is a promising strategy for colorectal cancer.
- This approach enhances antitumor efficacy by modulating tumor cells and the immune microenvironment while minimizing systemic toxicity.
