An Ingenious Peroxynitrite Generator Specifically Reversing “Cold” Tumors via Pyroptosis and STING Pathways

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.