An Ingenious Peroxynitrite Generator Specifically Reversing "Cold" Tumors via Pyroptosis and STING Pathways
Ruipeng Li1, Chuangxin Zhang1, Yunxia Wang1
1School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan, P. R. China.
Abstract:
Peroxynitrite (ONOO-), as the most active species of nitrogen oxides, shows the powerful potential in treating "cold" tumors. Currently, the in vivo generating efficiency of ONOO- and triggering lethal pattern against tumor cells are the greatest challenges. Herein, an ingenious ONOO- generator (DBTG) is first synthesized by covalently linking reactive oxygen species donor (Nile blue derivative) and nitric oxide donor (arginine analog) in a single molecule to improve production of ONOO-. Lysosome-targeted DBTG is demonstrated to rapidly generate ONOO- to induce lysosomal membrane permeabilization and simultaneously trigger pyroptosis and cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway of tumor cells, dramatically promoting the infiltration of T cells and NK cells, and converting "cold" tumors into "hot" tumors. In vitro and in vivo experiments show that DBTG possesses significant anti-tumor efficacy, which not only provides a template for the design of novel drug molecules but also an effective strategy for the reversal of immunosuppressive microenvironment by the powerful inflammation triggered by pyroptosis and the STING pathways.
Insights
This study introduces DBTG, a novel molecule that generates peroxynitrite (ONOO-) to effectively treat tumors. DBTG converts cold tumors into hot tumors by triggering cell death and immune responses.
Area of Science:
- Biochemistry
- Immunology
- Materials Science
Background:
- Peroxynitrite (ONOO-) is a potent reactive nitrogen species with potential for treating "cold" tumors.
- Challenges in tumor treatment include low in vivo ONOO- generation efficiency and ineffective tumor cell killing.
- Developing strategies to enhance ONOO- production and induce tumor cell death is crucial.
Purpose of the Study:
- To synthesize and evaluate an ingenious ONOO- generator (DBTG) for enhanced anti-tumor efficacy.
- To investigate DBTG's mechanism in triggering tumor cell death and immune responses.
- To explore DBTG as a strategy for converting "cold" tumors into "hot" tumors.
Main Methods:
- Covalent linkage of a reactive oxygen species donor and a nitric oxide donor to create DBTG.
- Lysosome-targeted delivery of DBTG to tumor cells.
- In vitro and in vivo experiments to assess ONOO- generation, tumor cell death (pyroptosis), immune cell infiltration, and anti-tumor effects.
- Evaluation of the cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway activation.
Main Results:
- DBTG efficiently generates ONOO- in tumor cells, inducing lysosomal membrane permeabilization.
- DBTG triggers pyroptosis and activates the cGAS-STING pathway, promoting T cell and NK cell infiltration.
- DBTG demonstrates significant in vitro and in vivo anti-tumor efficacy, converting "cold" tumors to "hot" tumors.
- DBTG effectively reverses the immunosuppressive tumor microenvironment.
Conclusions:
- DBTG serves as an effective ONOO- generator for cancer therapy.
- DBTG's mechanism involves inducing pyroptosis and activating the cGAS-STING pathway, leading to enhanced anti-tumor immunity.
- DBTG offers a promising strategy for developing novel anti-cancer drugs and overcoming tumor immunosuppression.
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