A hybrid nanomodulator enables metabolic microenvironment remodeling for potent immunotherapy against lung adenocarcinoma

STING agonist-based immunotherapy holds considerable promise for cancer treatment, yet its efficacy against immunologically “cold” tumors such as lung adenocarcinoma (LUAD) remains markedly limited. A major obstacle lies in the highly glycolytic tumor microenvironment (TME), where Warburg effect-driven metabolic competition deprives immune cells of adequate energetic support and thereby compromises their antitumor activity. Herein, we develop a metabolism regulation-based STING-activating hybrid nano-regulator (Que@ZnPDA) for sensitized immunotherapy against LUAD. Upon intravenous administration, Que@ZnPDA undergoes GSH-responsive disassembly in the TME to release quercetin (Que) and Zn 2+ . Que suppresses glycolysis through downregulating MCT4, whereas Zn 2+ inhibits mitochondrial complex IV activity to restrain oxidative phosphorylation, leading to concurrent disruption of energy-supplying pathways in tumor cells. The resulting energy depletion directly impairs tumor cell survival and relieves metabolic pressure within the TME. Meanwhile, Zn 2+ activates the cGAS-STING pathway, while glycolysis inhibition-induced TREX1 downregulation and mitochondrial damage further elevate cGAS expression, thus strengthening STING signaling and promoting cytokine secretion to reverse the immunosuppressive microenvironment. This metabolism regulation-based hybrid nano-regulator provides a promising strategy for LUAD immunotherapy.